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Background: Hip osteoarthritis patients display higher levels of fatty infiltration (FI) in the gluteus minimus (GM) compared to other hip muscles. We investigated specific histological factors such as fiber type composition and collagen deposition, and functional outcomes like muscle strength and activation associated with FI in these patients., Methods: In twelve men (67 ± 6 y) undergoing total hip replacement (THR), hip and knee muscle strength and activation (electromyography, EMG) were assessed bilaterally. Magnetic resonance imaging (MRI) was used to compare the relative FI area and muscle cross sectional area (CSA) of the GM, rectus femoris (RF), tensor fascia latae (TFL) and vastus lateralis (VL). Adipocyte content, fiber type composition, grouping, fiber size, centrally nucleated fiber frequency, collagen deposition, satellite cell density and capillarization were assessed in intraoperative biopsies of the four muscles. Differences between GM and other muscles were assessed with repeated-measures one-way ANOVA followed by Dunnett's post-hoc test. Pearson coefficients were calculated for the correlations between FI measurements and the other histological and functional parameters., Results: Strength was lower in the affected limb. Knee extensor weakness was accompanied by lower VL muscle activation. Muscle CSA and FI did not differ between sides. In the affected limb, GM displayed larger relative FI area (MRI) compared to RF and VL. Biopsy adipocyte content was higher in GM than RF and TFL. Compared to the other hip muscles, GM displayed higher type 1 fiber content while its type 2X fiber content was lower. Fiber grouping levels were higher in GM than the other muscles. Collagen content was higher in GM than TFL and VL.  FI in GM was associated with type 1 (r = 0.43) and type 2X (r = -0.34) fiber content, fiber grouping (r = 0.39), and collagen deposition (r = 0.37). FI in VL was negatively associated with maximal knee extension strength (r = -0.65)., Conclusions: In patients undergoing THR, the higher FI levels of GM compared to other hip muscles were associated with fiber type composition and grouping, and with higher collagen deposition. Experimental studies exploring these associations could potentially uncover new targets for the treatment of intramuscular FI and related impairments in muscle function., Trial Registration: KEK number: 2016-01852, date of registration: 12-4-2017., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted according to the Declaration of Helsinki and the protocol was approved by the Ethics Committee of the Canton of Zurich (KEK number: 2016–01852). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: This study aimed to validate alterations in the gene expression of DNA methylation-related enzymes and global methylation in the peripheral blood mononuclear cell (PBMC) and synovial tissues of animal hip osteoarthritis (OA) models., Methods: Animals were assigned to the control (no treatment), sham (25 µL of sterile saline), and OA (25 µL of sterile saline and 2 mg of monoiodoacetate) groups. Microcomputed tomography scan, histopathological assessment and pain threshold measurement were performed after induction. The mRNA expression of the DNA methylation machinery genes and global DNA methylation in the PBMC and hip synovial tissue were evaluated., Results: The OA group presented with hip joint OA histopathologically and radiologically and decreased pain threshold. The mRNA expression of DNA methyltransferase (Dnmt 3a), ten-eleven translocation (Tet) 1 and Tet 3 in the synovial tissue of the OA group was significantly upregulated. Global DNA methylation in the synovial tissue of the OA group was significantly higher than that of the control and sham groups., Conclusions: The intra-articular administration of monoiodoacetate induced hip joint OA and decreased pain threshold. The DNA methylation machinery in the synovial tissues of hip OA was altered., (© 2024. The Author(s).)

Primary hip osteoarthritis (pOA) develops without an apparent underlying reason, whereas secondary osteoarthritis arises due to a known cause, such as developmental dysplasia of the hips (DDH-OA). DDH-OA patients undergo total hip arthroplasty at a much younger age than pOA patients (50.58 vs. 65 years in this study). Recently, mesenchymal stem and progenitor cells (MSPCs) have been investigated for the treatment of osteoarthritis due to their immunomodulatory and regenerative potential. This study identified cells in subchondral bone expressing common MSPC markers (CD10, CD73, CD140b, CD146, CD164, CD271, GD2, PDPN) in vivo and compared the proportions of these populations in pOA vs. DDH-OA, further correlating them with clinical, demographic, and morphological characteristics. The differences in subchondral morphology and proportions of non-hematopoietic cells expressing MSPC markers were noted depending on OA type and skeletal location. Bone sclerosis was more prominent in the pOA acetabulum (Ac) in comparison to the DDH-OA Ac and in the pOA Ac compared to the pOA femoral head (Fh). Immunophenotyping indicated diagnosis-specific differences, such as a higher proportion of CD164+ cells and their subsets in DDH-OA, while pOA contained a significantly higher proportion of CD10+ and GD2+ cells and subsets, with CD271+ being marginally higher. Location-specific differences showed that CD271+ cells were more abundant in the Fh compared to the Ac in DDH-OA patients. Furthermore, immunohistochemical characterization of stromal bone-adjacent cells expressing MSPC markers (CD10, CD164, CD271, GD2) in the Ac and Fh compartments was performed. This research proved that immunophenotype profiles and morphological changes are both location- and disease-specific. Furthermore, it provided potentially effective targets for therapeutic strategies. Future research should analyze the differentiation potential of subsets identified in this study. After proper characterization, they can be selectively targeted, thus enhancing personalized medicine approaches in joint disease management., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans' heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.

Osteoarthritis (OA), a late-stage complication of developmental dysplasia of the hip (DDH), is a key factor leading to further degeneration of joint function. Studies have shown that Sestrin2 (SESN2) is a positive regulator in protecting articular cartilage from degradation. However, the regulatory effects of SESN2 on DDH-OA and its upstream regulators remain obscure. Here, we first identified that the expression of SESN2 significantly decreased in the cartilage of DDH-OA samples, with an expression trend negatively correlated with OA severity. Using RNA sequencing, we identified that the upregulation of miR-34a-5p may be an important factor for the decrease in SESN2 expression. Further exploring the regulation mechanism of miR-34a-5p/SESN2 is of great significance for understanding the mechanism of DDH occurrence and development. Mechanistically, we showed that miR-34a-5p could significantly inhibit the expression of SESN2, thereby promoting the activity of the mTOR signaling pathway. We also found that miR-34a-5p significantly inhibited SESN2-induced autophagy, thereby suppressing the proliferation and migration of chondrocytes. We further validated that knocking down miR-34a-5p in vivo resulted in a significant increase in SESN2 expression and autophagy activity in DDH-OA cartilage. Our study suggests that miR-34a-5p is a negative regulator of DDH-OA, and may provide a new target for the prevention of DDH-OA., (© 2023 Orthopaedic Research Society.)

Femoroacetabular impingement (FAI) is an important trigger of hip osteoarthritis (OA). Epigenetic changes in DNA methyltransferase 3B (DNMT3B) attenuate catabolic gene expression in cartilage hemostasis. This study aimed to examine the articular chondrocyte catabolic state and DNMT3B and 4-aminobutyrate aminotransferase promoter (ABAT) expression during OA progression in FAI. Cartilage samples were collected from the impingement zone of 12 patients with cam FAI (early-FAI) and 12 patients with advanced OA secondary to cam FAI (late-FAI-OA). Five healthy samples were procured from cadavers (ND: nondiseased). Explants were cultured under unstimulated conditions, catabolic stimulus (IL1β), or anabolic stimulus (TGFβ). Histology was performed with safranin-O/fast-green staining. Gene expression was analyzed via qPCR for GAPDH, DNMT3B, ABAT, MMP-13, COL10A1. Methylation specific PCR assessed methylation status at the ABAT promoter. Cartilage samples in early-FAI and late-FAI-OA showed a histological OA phenotype and increased catabolic marker expression (MMP13/COL10A1, ND vs. early-FAI, p = 0.004/p < 0.001, ND vs. late-FAI-OA, p < 0.001/p < 0.001). RT-PCR confirmed DNMT3B underexpression (ND vs. early-FAI, p < 0.001, early-FAI vs. late-FAI-OA, p = 0.016) and ABAT overexpression (ND vs. early-FAI, p < 0.001, early vs. late-FAI-OA, p = 0.035) with advanced disease. End-stage disease showed ABAT promoter hypomethylation. IL1β stimulus accentuated ABAT promoter hypomethylation and led to further ABAT and catabolic marker overexpression in early-FAI and late-FAI-OA while TGFβ normalized these alterations in gene expression. Catabolic and epigenetic molecule expression suggested less catabolism in early-stage disease. Sustained inflammation induced ABAT promoter hypo-methylation causing a catabolic phenotype. Suppression of ABAT by methylation control could be a new target for therapeutic intervention to prevent OA progression in hip FAI., (© 2023 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Femoroacetabular impingement (FAI) has a strong clinical association with the development of hip osteoarthritis (OA); however, the pathobiological mechanisms underlying the transition from focal impingement to global joint degeneration remain poorly understood. The purpose of this study is to use whole-genome RNA sequencing to identify and subsequently validate differentially expressed genes (DEGs) in femoral head articular cartilage samples from patients with FAI and hip OA secondary to FAI. Thirty-seven patients were included in the study with whole-genome RNA sequencing performed on 10 gender-matched patients in the FAI and OA cohorts and the remaining specimens were used for validation analyses. We identified a total of 3531 DEGs between the FAI and OA cohorts with multiple targets for genes implicated in canonical OA pathways. Quantitative reverse transcription-polymerase chain reaction validation confirmed increased expression of FGF18 and WNT16 in the FAI samples, while there was increased expression of MMP13 and ADAMTS4 in the OA samples. Expression levels of FGF18 and WNT16 were also higher in FAI samples with mild cartilage damage compared to FAI samples with severe cartilage damage or OA cartilage. Our study further expands the knowledge regarding distinct genetic reprogramming in the cartilage between FAI and hip OA patients. We independently validated the results of the sequencing analysis and found increased expression of anabolic markers in patients with FAI and minimal histologic cartilage damage, suggesting that anabolic signaling may be increased in early FAI with a transition to catabolic and inflammatory gene expression as FAI progresses towards more severe hip OA. Clinical significance:Cam-type FAI has a strong clinical association with hip OA; however, the cellular pathophysiology of disease progression remains poorly understood. Several previous studies have demonstrated increased expression of inflammatory markers in FAI cartilage samples, suggesting the involvement of these inflammatory pathways in the disease progression. Our study further expands the knowledge regarding distinct genetic reprogramming in the cartilage between FAI and hip OA patients. In addition to differences in inflammatory gene expression, we also identified differential expression in multiple pathways involved in hip OA progression., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

The acetabular labrum enhances hip joint stability and plays a key role in osteoarthritis (OA) progression. Labral nerve endings contribute to hip OA pain. Moreover, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) are associated with pain. Consequently, we analysed VEGF and NGF expression levels in the labrum and their roles in OA. Labra obtained from OA patients were stained immunohistochemically, and labral cells were cultured and subjected to a reverse transcription (RT)-polymerase chain reaction (PCR) to analyse VEGF and NGF mRNA expression. VEGF and NGF expression were compared in each region of the labrum. Correlations between VEGF and NGF expression and age, body mass index, Kellgren-Lawrence grade, Harris Hip Score, the visual analogue scale (VAS), and Krenn score were analysed, and the RT-PCR confirmed the findings. VEGF and NGF expression were high on the labral articular side, negatively correlated with the Krenn score, and positively correlated with the VAS in early OA. VEGF and NGF mRNA expression increased significantly in patients with severe pain and decreased significantly in severely degenerated labra. In early OA, VEGF and NGF expression in the acetabular labrum was associated with the occurrence of hip pain; therefore, these factors could be effective targets for pain management.

Hyaluronan (HA) plays crucial roles in the maintenance of high-quality cartilage extracellular matrix. Several studies have reported the HA in synovial fluid in patients with osteoarthritis (OA), but few have described the changes of HA in articular cartilage of OA or idiopathic osteonecrosis of the femoral head (ONFH). KIAA1199 was recently reported to have strong hyaluronidase activity. The aim of this study was to clarify the HA metabolism in OA and ONFH, particularly the involvement of KIAA1199. Immunohistochemical analysis of KIAA1199 and HA deposition was performed for human OA (n = 10), ONFH (n = 10), and control cartilage (n = 7). The concentration and molecular weight (MW) of HA were determined by competitive HA ELISA and Chromatography, respectively. Regarding HA metabolism-related molecules, HAS1, HAS2, HAS3, HYAL1, HYAL2, and KIAA1199 gene expression was assessed by reverse transcriptase polymerase chain reaction. Histological analysis showed the overexpression of KIAA1199 in OA cartilage, which was accompanied by decreased hyaluronic acid binding protein (HABP) staining compared with ONFH and control. Little KIAA1199 expression was observed in cartilage at the collapsed area of ONFH, which was accompanied by a slight decrease in HABP staining. The messenger RNA (​​​​​mRNA) expression of HAS2 and KIAA1199 was upregulated in OA cartilage, while the mRNA expression of genes related to HA catabolism in ONFH cartilage showed mostly a downward trend. The MW of HA in OA cartilage increased while that in ONFH cartilage decreased. HA metabolism in ONFH is suggested to be generally indolent, and is activated in OA including high expression of KIAA1199. Interestingly, MW of HA in OA cartilage was not reduced., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Objective: To evaluate IL-1 and C-reactive protein (CRP) levels in the synovial fluid in dogs with bilateral hip osteoarthritis and their relation to animals' clinical, radiographic, and thermographic disease signs., Sample: 100 joints from police working dogs., Procedures: Synovial fluid, IL-1, and CRP levels, weight distribution, joint range of motion, thigh girth, digital thermography, and radiographic signs of the joints were recorded. Data from 4 clinical metrology instruments (CMIs) were collected. Results were compared by age, sex, and Orthopedic Foundation for Animals hip scores with the independent samples t test, ANOVA, and Pearson correlation coefficient (P < .05)., Results: The sample included 100 pelvic limbs, equally distributed between left and right pelvic limbs 30 males and 20 females, with a mean age of 6.5 ± 2.4 years and body weight of 26.7 ± 5.2 kg. IL-1 levels, particularly above 200 pg/mL, may be related to the development of caudolateral curvilinear osteophyte, which then expresses a toll on the patient's levels of pain and activity. It was unclear if the CRP levels were a consequence of inflammatory activity within the joint or a reflection of a better prognosis. Increasing body weight was related to worse CMI scores., Clinical Relevance: We described the relation of IL-1 and CRP synovial concentration levels with several clinical signs, diagnostic imaging, laboratory findings, and CMI results of animals with osteoarthritis. Further studies are required to determine the interest of each parameter for the prognosis and treatment monitoring.

We investigated the analgesic effects of tramadol and the arthritic changes following tramadol administration in the rat hip osteoarthritis (OA) model using mono-iodoacetate (MIA). The right hip joints of male Sprague-Dawley rats (n = 5 rats/group) in the Sham group were injected with 25 μl of sterile saline and 1% of fluorogold (FG) retrograde neurotracer. In the MIA + Vehicle and MIA + Tramadol groups, FG and 25 μl of sterile saline with 0.5 mg of MIA were injected into the right hip joint. The MIA + Vehicle and MIA + Tramadol groups were administered daily for 4 weeks, either sterile saline (10 mg/kg, intraperitoneal [i.p.]) or tramadol (10 mg/kg, i.p.). We assessed hyperalgesia every week after MIA administration. Histopathological changes and immunoreactive neurons for calcitonin gene-related peptide (CGRP) in dorsal root ganglia (DRG) were evaluated after 4 weeks of treatment. MIA injection into the hip joint led to mechanical hyperalgesia (p < 0.01), which was significantly reduced by tramadol administration (p < 0.01). Furthermore, daily i.p injection of tramadol significantly suppressed CGRP expression in DRG (p < 0.0001). MIA + Vehicle and MIA + Tramadol groups showed significant cartilage reduction and degeneration compared to the Sham group (p < 0.0001). Interestingly, OA changes significantly progressed in the MIA + Tramadol group compared to the MIA + Vehicle group (p < 0.0001)., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Objective: Hip osteoarthritis (OA) affects all components of the osteochondral unit, leading to bone marrow (BM) lesions, and unknown consequences on BM cell functionality. We analyzed the cellular composition in OA-affected acetabula compared to proximal femur shafts obtained of hip OA patients to reveal yet not explored immune and stem cell compartments., Design: Combining flow cytometry, cellular assays and transcription analyses, we performed extensive ex vivo phenotyping of acetabular BM cells from 18 hip OA patients, comparing them with their counterparts from patient-matched femoral shaft BM samples. Findings were related to differences in skeletal sites and age., Results: Acetabular BM had a greater frequency of T-lymphocytes, non-hematopoietic cells and colony-forming units fibroblastic potential than femoral BM. The incidence of acetabular CD45 + CD3 + T-lymphocytes increased (95% CI: 0.1770 to 0.0.8416), while clonogenic hematopoietic progenitors declined (95% CI: -0.9023 to -0.2399) with age of patients. On the other side, in femoral BM, we observed higher B-lymphocyte, myeloid and erythroid cell frequencies. Acetabular mesenchymal stromal cells (MSCs) showed a senescent profile associated with the expression of survival and inflammation-related genes. Efficient osteogenic and chondrogenic differentiation was detected in acetabular MSCs, while adipogenesis was more pronounced in their femoral counterparts., Conclusion: Our results suggest that distinctions in BM cellular compartments and MSCs may be due to the influence of the OA-stressed microenvironment, but also acetabular vs femoral shaft-specific peculiarities cannot be excluded. These results bring new knowledge on acetabular BM cell populations and may be addressed as novel pathogenic mechanisms and therapeutic targets in OA., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Expression of CD163, a scavenger receptor specifically expressed by monocytes and macrophages, is elevated in the synovial tissue of patients with knee osteoarthritis (OA) compared with healthy controls. However, the association between CD163 expression in the synovium and pain in OA patients is unclear. We investigated the correlation between synovial CD163 expression and resting and active pain levels in patients with hip osteoarthritis (HOA). To investigate the possible contribution of CD163+ subsets to pain pathogenesis, we compared pain-related cytokine expression and M1/M2 macrophage marker expression in CD163+ and CD163- cells. We performed flow cytometric analysis to study the CD163+ cell population. We also examined pain-related cytokine expression and M1/M2 macrophage marker expression on CD163+ CD14 high and CD163+ CD14 low cells using cell sorting. Synovial CD163 expression significantly correlated with resting pain levels (p = 0.006; R = 0.321), but not active pain levels (p = 0.155; R = 0.169). Expression of the M1 macrophage marker CD80 was significantly higher in CD163+ than CD163- cells (p = 0.010), as was the expression of M2 macrophage markers CD206 and IL10 (CD206, p = 0.014; IL10, p = 0.005), and TNFA and IL1B (TNFA, p = 0.002; IL1B, p = 0.001). TNFA expression was significantly higher in CD163+ CD14 low than CD163+ CD14 high cells, while IL1B, IL10, and CD206 expression were comparable among these subsets. Our findings suggest that CD163 expression is associated with higher resting pain scores. As TNF-α plays a role in the pain process, CD163+ CD14 low cells expressing TNFA may be a potent contributor to the pathogenesis of resting pain in HOA., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: The pathogenesis of Ankylosing spondylitis (AS) has not been elucidated, especially involving hip joint disease. The purpose of this study was to analyze the proteome of diseased hip in AS and to identify key protein biomarkers., Material and Methods: We used label-free quantification combined with liquid chromatography mass spectrometry (LC-MS/MS) to screen for differentially expressed proteins in hip ligament samples between AS and No-AS groups. Key protein was screened by Bioinformatics methods. and verified by in vitro experiments., Results: There were 3,755 identified proteins, of which 92.916% were quantified. A total of 193 DEPs (49 upregulated proteins and 144 downregulated proteins) were identified according to P < 0.01 and Log|FC| > 1. DEPs were mainly involved in cell compartment, including the vacuolar lumen, azurophil granule, primary lysosome, etc. The main KEGG pathway included Phagosome, Glycerophospholipid metabolism, Lysine degradation, Pentose phosphate pathway. Myeloperoxidase (MPO) was identified as a key protein involved in Phagosome pathway. The experiment of siRNA interfering with cells further confirmed that the upregulated MPO may promote the inflammatory response of fibroblasts., Conclusions: The overexpression of MPO may contribute to the autoimmune inflammatory response of AS-affected hip joint through the phagosome pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yu, Zhan, Liang, Chen, Zhang, Jiang, Xue, Chen and Liu.)

Objective: Osteonecrosis of the femoral head (ONFH) is a devastating disease of the hip joint. Its early diagnosis is crucial to increase the chances of joint preserving, yet difficult due to similarities with osteoarthritis (OA) of the hip in its clinical appearance. The purpose of this study was to enhance the understanding of ONFH and its pathologic processes in contrast to OA and to identify serum biomarkers helping to improve the diagnosis of the disease., Design: Bone and bone marrow samples were collected from 24 patients diagnosed with OA and 25 patients with ONFH during total hip replacement surgery. RNA was isolated, histological examination, determination of free reactive oxygen species as well as gene expression and biomarker analysis were performed., Results: Histological analysis revealed differences in the structural and cellular pattern between the groups. Gene expression analysis revealed a significant upregulation for the genes ASPN, COL1A1, COL2A1 and IL6 and a significant downregulation for HIF1A in ONFH compared to OA group. Analysis of serum biomarkers showed significant differences between the groups for asporin and adiponectin. A final logistical regression model including the parameters adiponectin, asporin and HIF 1α was overall significant, explained 34.5 % of variance and classified 74.5 % of the cases correctly., Conclusion: The combination of adiponectin, asporin and HIF 1α as serum biomarkers revealed a classification accuracy of 74.5 %. The information provided in this study may help to enhance the understanding of pathologic processes in ONFH and to elaborate further aspects of prediction and treatment., (Copyright © 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Obesity increases the risk of hip osteoarthritis (OA). Recent studies have shown that adipokine extracellular nicotinamide phosphoribosyltransferase (eNAMPT or visfatin) induces the production of IL-6 and matrix metalloproteases (MMPs) in chondrocytes, suggesting it may promote articular cartilage degradation. However, neither the functional effects of extracellular visfatin on human articular cartilage tissue, nor its expression in the joint of hip OA patients of varying BMI, have been reported. Hip OA joint tissues were collected from patients undergoing joint replacement surgery. Cartilage explants were stimulated with recombinant human visfatin. Pro-inflammatory cytokines and MMPs were measured by ELISA and Luminex. Localisation of visfatin expression in cartilage tissue was determined by immunohistochemistry. Cartilage matrix degradation was determined by quantifying proteoglycan release. Expression of visfatin was elevated in the synovial tissue of hip OA patients who were obese, and was co-localised with MMP-13 in areas of cartilage damage. Visfatin promoted the degradation of hip OA cartilage proteoglycan and induced the production of pro-inflammatory cytokines (IL-6, MCP-1, CCL20, and CCL4) and MMPs. The elevated expression of visfatin in the obese hip OA joint, and its functional effects on hip cartilage tissue, suggests it plays a central role in the loss of cartilage integrity in obese patients with hip OA.

Objective: To identify OA subtypes based on cartilage transcriptomic data in cartilage tissue and characterize their underlying pathophysiological processes and/or clinically relevant characteristics., Methods: This study includes n = 66 primary OA patients (41 knees and 25 hips), who underwent a joint replacement surgery, from which macroscopically unaffected (preserved, n = 56) and lesioned (n = 45) OA articular cartilage were collected [Research Arthritis and Articular Cartilage (RAAK) study]. Unsupervised hierarchical clustering analysis on preserved cartilage transcriptome followed by clinical data integration was performed. Protein-protein interaction (PPI) followed by pathway enrichment analysis were done for genes significant differentially expressed between subgroups with interactions in the PPI network., Results: Analysis of preserved samples (n = 56) resulted in two OA subtypes with n = 41 (cluster A) and n = 15 (cluster B) patients. The transcriptomic profile of cluster B cartilage, relative to cluster A (DE-AB genes) showed among others a pronounced upregulation of multiple genes involved in chemokine pathways. Nevertheless, upon investigating the OA pathophysiology in cluster B patients as reflected by differentially expressed genes between preserved and lesioned OA cartilage (DE-OA-B genes), the chemokine genes were significantly downregulated with OA pathophysiology. Upon integrating radiographic OA data, we showed that the OA phenotype among cluster B patients, relative to cluster A, may be characterized by higher joint space narrowing (JSN) scores and low osteophyte (OP) scores., Conclusion: Based on whole-transcriptome profiling, we identified two robust OA subtypes characterized by unique OA, pathophysiological processes in cartilage as well as a clinical phenotype. We advocate that further characterization, confirmation and clinical data integration is a prerequisite to allow for development of treatments towards personalized care with concurrently more effective treatment response., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Dysregulation of circular RNAs (circRNAs) is involved in various human diseases. Fibroblast-like synoviocytes (FLSs), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype and contribute to joint destruction in rheumatoid arthritis (RA). In the present study, we identified a novel circRNA, Circ&#95;0088194, which was upregulated in RA fibroblast-like synoviocytes (RA-FLSs) and correlated with the disease activity score in 28 joints. Overexpression of Circ&#95;0088194 promoted RA-FLS migration and invasion, while inhibition of Circ&#95;0088194 had the opposite effect. Mechanistically, Circ&#95;0088194 acted as a miR-766-3p sponge to relieve the repressive effect of miR-766-3p on its target, MMP2 (encoding matrix metalloproteinase 2), thereby promoting migration and invasion. The expression level of Circ&#95;0088194 was inversely correlated with that of miR-766-3p in RA-FLSs. Importantly, overexpression of miR-766-3p partially blocked the migration and invasion induced by Circ&#95;0088194 overexpression. Collectively, this study identified a novel circRNA Circ&#95;0088194 that promotes RA-FLS invasion and migration via the miR-766-3p/MMP2 axis. Circ&#95;0088194 might represent a novel therapeutic target to prevent and treat RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cai, Liang, Xiao, Huang, Zhu, Shi, Ouyang and Yang.)

Hip osteoarthritis (HOA) is characterized by degradation of the cartilage and synovitis. However, the pathohistological effects of synovial tissue inflammation on HOA are not clear. The aim of this study was to evaluate the expression of iNOS, BCL-2 and MMP-9 markers in different synovial cell populations. A total of 32 patients were evaluated retrospectively. Age, sex, height, weight, body mass index were recorded and lymphocyte, fibrocytes and macrophages were analysed in tissue sections. Osteoarthritis cartilage histopathology assessment system (OARSI), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Krenn score, Harris Hip Score (HHS) and Kellgren-Lawrence (K-L) grading of the hip joints were performed. Total hip arthroplasty was performed on 32 patients and controls. Patients were divided into two groups according to their disease severity. The tissues were immunohistochemically analysed. K-L grade and Krenn score differ between all three groups, but also between moderate and severe OA. Synovial lining cell layer, resident cells in stroma and especially inflammatory infiltration were increasing with severity of OA. iNOS expression in both intima and subintima was positively correlated with Krenn score in moderate and severe osteoarthritis (OA) groups. Expression of BCL-2 in intima of severe OA patients was positively correlated with Krenn score. In conclusion, iNOS, BCL-2 and MMP-9 are involved in the regulation of HOA. Our study indicates a relationship between the pathohistological features, the synovial inflammation and the cartilage condition at the time of hip replacement due to OA or femoral neck fracture.

Objective: To identify robustly differentially expressed long noncoding RNAs (lncRNAs) with osteoarthritis (OA) pathophysiology in cartilage and to explore potential target messenger RNA (mRNA) by establishing coexpression networks, followed by functional validation., Methods: RNA sequencing was performed on macroscopically lesioned and preserved OA cartilage from patients who underwent joint replacement surgery due to OA (n = 98). Differential expression analysis was performed on lncRNAs that were annotated in GENCODE and Ensembl databases. To identify potential interactions, correlations were calculated between the identified differentially expressed lncRNAs and the previously reported differentially expressed protein-coding genes in the same samples. Modulation of chondrocyte lncRNA expression was achieved using locked nucleic acid GapmeRs., Results: By applying our in-house pipeline, we identified 5,053 lncRNAs that were robustly expressed, of which 191 were significantly differentially expressed (according to false discovery rate) between lesioned and preserved OA cartilage. Upon integrating mRNA sequencing data, we showed that intergenic and antisense differentially expressed lncRNAs demonstrate high, positive correlations with their respective flanking sense genes. To functionally validate this observation, we selected P3H2-AS1, which was down-regulated in primary chondrocytes, resulting in the down-regulation of P3H2 gene expression levels. As such, we can confirm that P3H2-AS1 regulates its sense gene P3H2., Conclusion: By applying an improved detection strategy, robustly differentially expressed lncRNAs in OA cartilage were detected. Integration of these lncRNAs with differential mRNA expression levels in the same samples provided insight into their regulatory networks. Our data indicates that intergenic and antisense lncRNAs play an important role in regulating the pathophysiology of OA., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: In cartilage, the osteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates with differential expression of PLEC, and with differential methylation of PLEC CpG dinucleotides, forming eQTLs and mQTLs respectively. This implies that methylation links chondrocyte genotype and phenotype, thus driving the functional effect of this genetic risk signal. PLEC encodes plectin, a cytoskeletal protein that enables tissues to respond to mechanical forces. We sought to assess whether these PLEC functional effects were cartilage specific., Method: Cartilage, fat pad, synovium and peripheral blood were collected from patients undergoing arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) was performed to test for eQTLs. Plectin was knocked down in a mesenchymal stem cell (MSC) line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing., Results: mQTLs were discovered in fat pad, synovium and blood. Their effects were however stronger in the joint tissues and of comparable effect between these tissues. We observed AEI in synovium in the same direction as for cartilage and correlations between methylation and PLEC expression. Knocking-down plectin impacted on pathways reported to have a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune regulation., Conclusions: Synovium is also a target of the rs11780978 OA association functionally operating on PLEC. In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting the functional effect is not joint-wide. Our study highlights interplay between genetic risk, DNA methylation and gene expression in OA, and reveals clear differences between tissues from the same diseased joint., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Several plant polyphenols have been shown to reduce osteoarthritis symptoms due to their antioxidant, anti-inflammatory and immunomodulatory properties. We investigated the effects of two different polyphenolic extracts (Belinal, Pycnogenol) and two different polyphenols (resveratrol, quercetin) on the chondrogenic potential of bone-derived mesenchymal stem/stromal cells (MSCs) from healthy donors and patients with osteoarthritis. Our main aim was to determine whether Belinal, a commercially available polyphenolic extract from silver fir ( Abies alba L.) branches, has comparable chondrogenic potential with the other tested extract and the polyphenols under inflammatory and non-inflammatory conditions. In our study, Belinal promoted significantly greater chondrogenesis compared to the untreated ( p = 0.0289) and resveratrol-treated ( p = 0.0468) MSCs from patients with hip osteoarthritis under non-inflammatory conditions. Under inflammatory conditions, chondrogenesis was significantly enhanced for MSCs treated with Belinal compared to the control ( p = 0.0483). The other extract and the polyphenols did not show any significant effects on chondrogenesis under non-inflammatory or inflammatory conditions. None of the tested extracts and polyphenols showed significant effects on chondrogenesis in healthy donors, under either non-inflammatory or inflammatory conditions. Our data show that Belinal can boost the chondrogenesis of MSCs derived from patients with osteoarthritis, under both non-inflammatory and inflammatory conditions.

Developmental dysplasia of the hip (DDH) represents a morphological abnormality characterized by the incongruity of femoral head and acetabulum. It ranges from mild dysplastic changes to complete dislocation. DDH has been associated with several hereditary and environmental risk factors, which could explain the incidence variability among different countries. Numerous genes may be involved in the disease etiology and progression. However, there are controversies in the literature regarding some of these genes. DDH-induced secondary osteoarthritis (OA) is characterized by changes in the macromolecule content of the cartilage and the expression of cartilage degradation markers. In addition, it exhibits a pattern of specific histological changes, with several reported differences between primary and DDH-induced secondary OA. The articular cartilage of patients with DDH shows specific radiological characteristics, including changes visible already in infancy, but also at pre-arthritic stages, early stages of OA, and in fully developed DDH-induced secondary OA. Although DDH has been extensively researched in different disease stages, the etiology of the disorder still remains uncertain. This review focuses on the current knowledge on the histomorphological status of the cartilage and the genetic background of DDH.

Objective: The vascular invasion of cartilage is an essential process in the endochondral ossification of long bones. In contrast, vascularization of articular cartilage constitutes a pathological mechanism in the development of osteoarthritis. Polymorphisms of Col9a1 have been described as risk factors for hip osteoarthritis (OA) and the loss of collagen IX is known to lead to premature OA of the hip joint in mice but the underlying mechanism is so far unknown., Design: To understand the contribution of collagen IX to OA development in the hip joint, we analyzed the early development of murine Col9a1 -/- femoral heads between newborn stage and 16 weeks of age., Results: We found significantly accelerated ossification of the femoral heads in the absence of collagen IX as well as premature vascular and osteoclast invasion, even though hypertrophic differentiation was delayed. The loss of collagen IX led to anatomically altered femoral heads lacking the epiphyseal tubercle. Interestingly, this region was found to contain highest levels of the antiangiogenic protein thrombospondin-1 (TSP-1). Hence, TSP-1 levels were strongly reduced in the Col9a1 -/- femoral heads. In addition, antiangiogenic matrilin-1 was found to be decreased, while proangiogenic active MMP-9 levels were increased in the collagen IX deficient mice compared to wildtype controls., Conclusion: We conclude that collagen IX protects against premature vascularization and cartilage to bone transition in femoral heads by increasing the levels of antiangiogenic TSP-1 and matrilin-1 and decreasing the levels of proangiogenic active MMP-9., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Aim: To assess tissue level changes of proteome and cytokine profiles of subchondral bone in hip osteoarthritis (OA) affected by bone marrow lesions (BMLs). We compared significant protein level differences in osteoarthritic bone with BMLs to control bone without bone marrow lesions., Methods: Subchondral bone biopsies were taken from femoral heads of end-stage osteoarthritis patients with (BML, n = 21) and without (CON, n = 9) BMLs. Proteins were extracted through a standardized Trizol protocol and used in the subsequent analyses. Angiogenesis and bone markers were assessed using multiplex immunoassays (Luminex). Liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to detect significant differences in proteome and peptide profiles between BML and CON., Results: Multiplex immunoassays revealed increased tissue contents of vascular endothelial growth factors (VEGF-A/C/D), endothelin-1, angiopoietin-2 and interleukin-6 (IL-6) in bone with BMLs compared to control bone, whereas osteoprotegerin levels were reduced. Mass spectrometry demonstrated pronounced increase in the levels of hemoglobin (73-fold), serum albumin (30-fold), alpha-1-antitrypsin (9-fold), apolipoprotein A1 (4.7-fold), pre-laminin-A/C (3.7-fold) and collagen-alpha1-XII (3-fold) in BMLs, while aggrecan core protein (ACAN) and hyaluronan and proteoglycan link protein 1 (HAPL1) decreased 37- and 29-fold respectively., Conclusion: Reduced osteoprotegerin, ACAN and HAPL1 are consistent with osteoclastic activation and high remodeling activity in BMLs. The pronounced increase in angiogenesis markers, hemoglobin and serum albumin support the presence of increased vascularity in subchondral bone affected by BMLs in OA. VEGFs and IL-6 are known nociceptive modulators, and increased levels are in keeping with pain being a clinical feature frequently associated with BMLs., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Femoroacetabular impingement (FAI) has been proposed as an etiologic factor in up to 50% of hips with osteoarthritis (OA). Inflammation is thought to be one of the main initiators of OA, yet little is known about the origin of intra-articular inflammation in FAI hips., Hypothesis: Articular cartilage from the impingement zone of patients with FAI has high levels of inflammation, reflecting initial inflammatory process in the hip., Study Design: Controlled laboratory study., Methods: Head-neck cartilage samples were obtained from patients with cam FAI (cam FAI, early FAI; n = 15), advanced OA secondary to cam FAI (FAI OA, late FAI; n = 15), and advanced OA secondary to developmental dysplasia of the hip (DDH OA, no impingement; n = 15). Cartilage procured from young adult donors (n = 7) served as control. Safranin O-stained sections were assessed for cartilage abnormality. Tissue viability was detected by TUNEL assay. Immunostaining of interleukin 1β (IL-1β), catabolic markers (matrix metalloproteinase 13 [MMP-13], a disintegrin and metalloproteinase with thrombospondin motif 4 [ADAMTS-4], aggrecan antibody to C-terminal neoepitope [NITEGE]), and an anabolic marker (type II collagen [COL2]) was performed to evaluate molecular inflammation and metabolic activity. The average percentage of immunopositive cells from the total cell count was calculated. Kruskal-Wallis test followed by Steel-Dwass post hoc test was used for multiple comparisons., Results: Microscopic osteoarthritic changes were more prevalent in cartilage of cam FAI and FAI OA groups compared with DDH OA and control groups. Cartilage in cam FAI and FAI OA groups, versus the DDH group, had higher expression of inflammatory molecules IL-1β (69.7% ± 18.1% and 72.5% ± 13.2% vs 32.7% ± 14.4%, respectively), MMP-13 (79.6% ± 12.6% and 71.4% ± 18.8% vs 38. 5% ± 13.3%), ADAMTS-4 (83.9% ± 12.2% and 82.6% ± 12.5% vs 45.7% ± 15.5%), and COL2 (93.6% ± 3.9% and 92.5% ± 5.8% vs 53.3% ± 21.0%) ( P < .001). Expression of NITEGE was similar among groups (cam FAI, 89.7% ± 7.7%; FAI OA, 95.7% ± 4.7%; DDH OA, 93.9% ± 5.2%; P = .0742). The control group had minimal expression of inflammatory markers. Inflammatory markers were expressed in all cartilage zones of early and late FAI but only in the superficial zone of the no impingement group., Conclusion: Cartilage from the impingement zone in FAI is associated with a high expression of inflammatory markers, extending throughout all cartilage zones., Clinical Relevance: Inflammation associated with FAI likely has a deleterious effect on joint homeostasis. Further clinical and translational studies are warranted to assess whether and how surgical treatment of FAI reduces molecular inflammation.

Objective: To identify long noncoding RNAs (lncRNAs) associated with the inflammatory phenotype of synovial fibroblasts from obese patients with osteoarthritis (OA), and to explore the expression and function of these lncRNAs., Methods: Synovium was collected from normal-weight patients with hip fracture (non-OA; n = 6) and from normal-weight (n = 8) and obese (n = 8) patients with hip OA. Expression of RNA was determined by RNA-sequencing and quantitative reverse transcription-polymerase chain reaction. Knockdown of lncRNA was performed using LNA-based GapmeRs. Synovial fibroblast cytokine production was measured by enzyme-linked immunosorbent assay., Results: Synovial fibroblasts from obese patients with OA secreted greater levels of interleukin-6 (IL-6) (mean ± SEM 162 ± 21 pg/ml; P < 0.001) and CXCL8 (262 ± 67 pg/ml; P < 0.05) compared to fibroblasts from normal-weight patients with OA (IL-6, 51 ± 4 pg/ml; CXCL8, 78 ± 11 pg/ml) or non-OA patients (IL-6, 35 ± 3 pg/ml; CXCL8, 56 ± 6 pg/ml) (n = 6 patients per group). RNA-sequencing revealed that fibroblasts from obese OA patients exhibited an inflammatory transcriptome, with increased expression of proinflammatory messenger RNAs (mRNAs) as compared to that in fibroblasts from normal-weight OA or non-OA patients (>2-fold change, P < 0.05; n = 4 patients per group). A total of 19 lncRNAs were differentially expressed between normal-weight OA and non-OA patient fibroblasts, and a further 19 lncRNAs were differentially expressed in fibroblasts from obese OA patients compared to normal-weight OA patients (>2-fold change, P < 0.05 for each), which included the lncRNA for metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1 was rapidly induced upon stimulation of OA synovial fibroblasts with proinflammatory cytokines, and was up-regulated in the synovium from obese OA patients as compared to normal-weight OA patients (1.6-fold change, P < 0.001) or non-OA patients (6-fold change, P < 0.001). MALAT1 knockdown in OA synovial fibroblasts (n = 4 patients) decreased the levels of mRNA expression and protein secretion of CXCL8 (>1.5-fold change, P < 0.01), whereas it increased expression of mRNAs for TRIM6 (>2-fold change, P < 0.01), IL7R (<2-fold change, P < 0.01), HIST1H1C (>1.5-fold change, P < 0.001), and MAML3 (>1.5-fold change, P < 0.001). In addition, MALAT1 knockdown inhibited the proliferation of synovial fibroblasts from obese patients with OA., Conclusion: Synovial fibroblasts from obese patients with hip OA exhibit an inflammatory phenotype. MALAT1 lncRNA may mediate joint inflammation in obese OA patients., (© 2019, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: Identifying objective risk-indicators for total joint replacement (TJR) is useful to enrich population at high risk in OA clinical trials. We investigate the association of urinary CTX-II, a biochemical marker of cartilage breakdown, with the risk of TJR., Method: 478 postmenopausal women (mean age 65.5 ± 7.5 yr) from the OFELY cohort were studied. CTX-II, serum CTX-I (bone resorption) and PINP (bone formation), were measured at baseline. Association between CTX-II and incidence of TJR was assessed by Cox Hazard Regression., Results: During a median (95%CI) 17.8 (15.0-18.1) years follow-up, 38 women sustained a TJR, including hip (n = 29) or knee (n = 9) replacement. CTX-II -but not CTX-I or PINP- was higher in patients with TJR (+34%, P = 0.001 vs women with no TJR). Increased baseline CTX-II levels were associated with a higher risk of TJR with a Hazard Ratio (HR) (95 CI) of 1.45 (1.13-1.85) per 1 SD increase after adjustment for age, BMI and total hip BMD. CTX-II remained significantly associated with the risk of TJR after further adjustment for total WOMAC, prevalent knee OA (KL ≥ 2) and self-reported hip OA [HR (95 CI): 1.31 (1.01-1.71), P = 0,04]. When women were categorized as low and high CTX-II (lower and above the 95 percentile of healthy premenopausal women, respectively), subjects with high levels had an age-BMI-hip BMD adjusted HR (95 CI) of 3.00 (1.54-5.85) compared to women with low levels which remained significant after further adjustment for WOMAC, knee and/or hip OA [HR (95 CI): 2.45 (1.25-4.89), P = 0.01]., Conclusion: CTX-II is an independent risk indicator of TJR in postmenopausal women suggesting that it may be useful to identify subjects at high risk of TJR., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Subjects with developmental dysplasia of the hip (DDH) often show early-onset osteoarthritis (OA); however, the molecular mechanisms underlying this pathology are not known. We investigated whether cellular changes in chondrocytes from OA cartilage can be detected in chondrocytes from DDH cartilage before histological manifestations of degeneration. We characterized undamaged and damaged articular cartilage from 22 participants having hip replacement surgery with and without DDH (9 DDH-OA, 12 OA-only, one femoral fracture). Tissue immunostaining revealed changes in damaged OA-only cartilage that was also found in undamaged DDH-OA cartilage. Chondrocytes in situ from both groups show: (i) thicker fibers of vimentin intermediate filaments, (ii) clusters of integrin α 5 β 1 , (iii) positive MMP13 staining and (iv) a higher percentage of cells expressing the serine protease HtrA1. Further characterization of the extracellular matrix showed strong aggrecan and collagen II immunostaining in undamaged DDH cartilage, with no evidence of augmented cell death by activation of caspase 3. These findings suggest that early events in DDH cartilage originate at the chondrocyte level and that DDH cartilage may provide a novel opportunity to study these early changes for the development of therapeutic targets for OA.

Background: Osteoarthritis is a chronic musculoskeletal disease characterized by age-related gradual thinning and a high risk in females. Recent studies have shown that DNA methylation plays important roles in osteoarthritis. However, the genome-wide pattern of methylation in enhancers in osteoarthritis remains unclear., Methods: To explore the function of enhancers in osteoarthritis, we quantified CpG methylation in human enhancers based on a public dataset that included methylation profiles of 470,870 CpG probes in 108 samples from patients with hip and knee osteoarthritis and hip tissues from healthy individuals. Combining various bioinformatics analysis tools, we systematically analyzed aberrant DNA methylation of the enhancers throughout the genome in knee osteoarthritis and hip osteoarthritis., Results: We identified 16,816 differentially methylated CpGs, and nearly half (8111) of them were from enhancers, suggesting major DNA methylation changes in both types of osteoarthritis in the enhancer regions. A detailed analysis of hip osteoarthritis identified 2426 differentially methylated CpGs in enhancers between male and female patients, and 84.5% of them were hypomethylated in female patients and enriched in phenotypes related to hip osteoarthritis in females. Next, we explored the enhancer methylation dynamics among patients with knee osteoarthritis and identified 280 differentially methylated enhancer CpGs that were enriched in the human phenotypes and disease ontologies related to osteoarthritis. Finally, a comparison of enhancer methylation between knee osteoarthritis and hip osteoarthritis revealed organ source-dependent differences in enhancer methylation., Conclusion: Our findings indicate that aberrant methylation of enhancers is related to osteoarthritis phenotypes, and a comprehensive atlas of enhancer methylation is useful for further analysis of the epigenetic regulation of osteoarthritis and the development of clinical drugs for treatment of osteoarthritis.

Bone diseases represent an increasing health burden worldwide, and basic research remains necessary to better understand the complexity of these pathologies and to improve and expand existing prevention and treatment approaches. In the present study, 216 bone samples from the caput femoris and collum femoris of 108 patients with degenerative or dysplastic coxarthrosis, hip fracture, or osteonecrosis were evaluated for the proportion of trabecular bone (TB) and expression of parathyroid hormone (PTH) type 1 receptor (PTH1R), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL). Serum levels of PTH, OPG, soluble RANKL (sRANKL), alkaline phosphatase (AP), osteocalcin, total procollagen type-1 intact N-terminal propeptide (TP1NP), tartrate-resistant acid phosphatase type 5b (TRAP5b), sclerostin, and C-telopeptide of type-1 collagen (ICTP) were also determined. Age was positively correlated with serum levels of PTH, OPG, and sclerostin but negatively associated with TB and sRANKL. Women exhibited less TB, lower sclerostin and ICTP, and higher TRAP5b. Impaired kidney function was associated with shorter bone decalcification time, less TB, lower sRANKL, and higher serum PTH, OPG, and sclerostin. Furthermore, correlations were observed between bone PTH1R and OPG expression and between serum PTH, OPG, and AP. There were also positive correlations between serum OPG and TP1NP; serum OPG and sclerostin; serum AP, osteocalcin, and TRAP5b; and serum sclerostin and ICTP. Serum OPG was negatively associated with sRANKL. In summary, clear relationships between specific bone metabolism markers were observed, and distinct influences of age, sex, and kidney function, thus underscoring their suitability as diagnostic or prognostic markers., Competing Interests: The authors have declared that no competing interests exist.

Objective: The hip and knee joints differ biomechanically in terms of contact stresses, fluid lubrication and wear patterns. These differences may be reflected in the synovial fluid (SF) composition of the two joints, but the nature of these differences remains unknown. The objective was to identify differences in osteoarthritic hip and knee SF metabolites using metabolic profiling with Nuclear Magnetic Resonance (NMR) spectroscopy., Design: Twenty-four SF samples (12 hip, 12 knee) were collected from patients with end-stage osteoarthritis (ESOA) undergoing hip/knee arthroplasty. Samples were matched for age, gender, ethnicity and had similar medical comorbidities. NMR spectroscopy was used to analyse the metabolites present in each sample. Principal Component Analysis and Orthogonal Partial Least Squares Discriminant Analysis were undertaken to investigate metabolic differences between the groups. Metabolites were identified using 2D NMR spectra, statistical spectroscopy and by comparison to entries in published databases., Results: There were significant differences in the metabolic profile between the groups. Four metabolites were found in significantly greater quantities in the knee group compared to the hip group (N-acetylated molecules, glycosaminoglycans, citrate and glutamine)., Conclusions: This is the first study to indicate differences in the metabolic profile of hip and knee SF in ESOA. The identified metabolites can broadly be grouped into those involved in collagen degradation, the tricarboxylic acid cycle and oxidative metabolism in diseased joints. These findings may represent a combination of intra and extra-articular factors., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) is a pathology characterized by the loss of articular cartilage. In this study, we performed a peptidomic strategy to identify endogenous peptides (neopeptides) that are released from human osteoarthritic tissue, which may serve as disease markers. With this aim, secretomes of osteoarthritic and healthy articular cartilages obtained from knee and hip were analyzed by shotgun peptidomics. This discovery step led to the identification of 1175 different peptides, corresponding to 101 proteins, as products of the physiological or pathological turnover of cartilage extracellular matrix. Then, a targeted multiple reaction monitoring-mass spectrometry method was developed to quantify the panel of best marker candidates on a larger set of samples ( n = 62). Statistical analyses were performed to evaluate the significance of the observed differences and the ability of the neopeptides to classify the tissue. Eight of them were differentially abundant in the media from wounded zones of OA cartilage compared with the healthy tissue ( p < 0.05). Three neopeptides belonging to Clusterin and one from Cartilage Oligomeric Matrix Protein showed a disease-dependent decrease specifically in hip OA, whereas two from Prolargin (PRELP) and one from Cartilage Intermediate Layer Protein 1 were significantly increased in samples from knee OA. The release of one peptide from PRELP showed the best metrics for tissue classification (AUC = 0.834). The present study reveals specific neopeptides that are differentially released from knee or hip human osteoarthritic cartilage compared with healthy tissue. This evidences the intervention of characteristic pathogenic pathways in OA and provides a novel panel of peptidic candidates for biomarker development., (© 2019 Fernández-Puente et al.)

Current evidence suggests a complex interaction between adipokines and microRNA (miRNA) in osteoarthritis (OA) pathogenesis. The present study explored the role of miR-34a and miR-181a in regulating apoptosis and oxidative stress induced by visfatin in human OA chondrocytes. Chondrocytes were transfected with miR-34a and miR-181a inhibitors and stimulated with visfatin for 24 h, in the presence of nuclear factor (NF)-κB inhibitor (BAY-11-7082, 2 h pre-incubation). Apoptosis and reactive oxygen species (ROS) production were detected by cytometry, miRNA, antioxidant enzymes, nuclear factor erythroid (NRF)2 and B-cell lymphoma (BCL)2 expressions by quantitative real time polymerase chain reaction (real time PCR) and western blot. P50 NF-κB subunit was measured by immunofluorescence. Visfatin significantly induced apoptosis and superoxide anion production, increased miR-34a, miR-181a, superoxide dismutase (SOD)-2, catalase (CAT), NRF2 and decreased BCL2 gene and protein expression in OA chondrocytes. All the visfatin-caused effects were suppressed by using miR-34a and miR-181a inhibitors. Pre-incubation with BAY-11-7082 counteracted visfatin-induced expression of miRNA, BCL2, SOD-2, CAT and NRF2. Inhibition of miR-34a and miR-181a significantly reduced the activation of p50 NF-κB. Visfatin confirms its ability to induce apoptosis and oxidative stress in human OA chondrocytes; these effects appeared mediated by miR-34a and miR-181a via NF-κB pathway. We highlight the relevance of visfatin as potential therapeutic target for OA treatment.

Background: Targeting new molecular pathways leading to Osteoporosis (OP) and Osteoarthritis (OA) is a hot topic for drug discovery. Clusterin (CLU) is a glycoprotein involved in inflammation, proliferation, cell death, neoplastic disease, Alzheimer disease and aging. The present study focuses on the expression and the role of CLU in influencing the decrease of muscle mass and fiber senescence in OP-OA condition., Methods: Vastus lateralis muscle biopsies were collected from 20 women with OP undergoing surgery for fragility hip fracture and 20 women undergoing arthroplasty for hip osteoarthritis., Results: We found an overexpression of CLU in degenerated fibers in OP closely correlated with interleukin 6 (IL6) and histone H4 acetylation level. Conversely, in OA muscle tissues we observed a weak expression of CLU but no nuclear histone H4 acetylation. Ex vivo studies on isolated human myoblasts confirmed CLU overexpression in OP as compared to OA (p < 0.001). CLU treatment of isolated OP and OA myoblasts showed: modulation of proliferation, morphological changes, increase of histone H4 acetylation and induction of myogenin (MYOG) activation in OP myoblast only. In OP condition, functional knockdown of CLU by siRNA restores proliferative myoblasts capability and tissue damage repair, carried out by an evident upregulation of Transglutaminase 2 (TGM2). We also observed downmodulation of CX3CR1 expression with consequent impairing of the inflammatory infiltrate recruitment., Conclusions: Results obtained suggest a potential role of CLU in OP by influencing myoblasts terminal differentiation, epigenetic regulation of muscle cell differentiation and senescence. Moreover, CLU silencing points out its role in the modulation of tissue damage repair and inflammation, proposing it as a new diagnostic marker for muscle degeneration and a potential target for specific therapeutic intervention in OP related sarcopenia.

Objective: Long intergenic non-coding RNAs (lincRNAs) are emerging as key regulators in gene expression; however, little is known about the lincRNA expression changes that occur in osteoarthritis (OA). Here we aimed to define a transcriptome of lncRNAs in OA cartilage, specifically comparing the lincRNA transcriptome of knee and hip cartilage., Method: RNA-seq was performed on nucleic acid extracted from hip cartilage from patients undergoing joint replacement surgery because of either OA (n = 10) or because of a neck of femur fracture (NOF; n = 6). After transcript alignment, counts were performed using Salmon and differential expression for ENSEMBL lincRNAs determined using DESeq2. Hip RNA-seq lincRNA expression was compared to a knee dataset (ArrayExpress; E-MTAB-4304). ChIP-seq data from ENCODE was used to determine whether lincRNAs were associated with promoters (plncRNA) or unidirectional enhancer-like regulatory elements (elncRNAs)., Results: Our analysis of the hip transcriptome identified 1692 expressed Transcripts Per Million (TPM ≥1) Ensembl lincRNAs, of which 198 were significantly (FDR ≤0.05) differentially expressed in OA vs normal (NOF) cartilage. Similar analysis of knee cartilage transcriptome identified 648 Emsembl lincRNAs with 93 significantly (FDR ≤0.05) differentially expressed in intact vs damaged cartilage. In total, 1834 lincRNAs were expressed in both hip and knee cartilage, with a highly significant correlation in expression between the two cartilages., Conclusion: This is the first study to use RNA-seq to map and compare the lincRNA transcriptomes of hip and knee cartilage. We propose that lincRNAs expressed selectively in cartilage, or showing differential expression in OA, will play a role in cartilage homoeostasis., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Canine hip dysplasia and developmental dysplasia of the human hip share demographic, phenotypic, and clinical features including the predisposition to develop osteoarthritis in affected joints. To support the results of genetic mapping studies for CHD and its concomitant osteoarthritis with functional information, we performed RNA-seq on hip capsule and teres ligament of affected and unaffected dogs. RNA seq showed that expressed genes segregated according age, capsule or ligament, and hip phenotype. Expression of HHIP, DACT2, and WIF1 was significantly higher in capsule from control hips than dysplastic hips indicating a disruption of the hedgehog signaling pathway. Expression of SPON 1, a key component of the WNT pathway, was increased significantly in both dysplastic capsule and ligament while FBN2 and EMILIN3 were significantly increased in dysplastic capsule. Of genes associated with human hip osteoarthritis, expression of ACAN, IGF1, CILP2, COL11A1, COL8A1, and HAPLN was increased significantly in dysplastic capsule. The significant increase in expression of PLA2F, TNFRSF, TMEM, and IGFBP in dysplastic capsule indicated an injury response. Gene set enrichment analysis revealed that genes involved in extracellular matrix structure, epithelial to mesenchymal transition, myogenesis, growth factor signaling, cancer and immune pathways were enriched in dysplastic capsule. For teres ligament from dysplastic joints, genes in retinoic signaling pathways and those encoding extracellular matrix molecules, but not proteoglycans, were enriched. Hip tissues respond to abnormal mechanics early in dysplastic hip development and these pathways present targets for intervention in the early synovitis and capsulitis secondary to canine and human hip dysplasia. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:313-324, 2019., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Osteoarthritis (OA) is a common chronic disease, causing joint pain and reduced physical function. OA progresses slowly over a period of several years; to avoid an exacerbation of symptoms, it is critical to able to diagnose the disease as early as possible. The identification of disease-specific biomarkers may enable such an early diagnosis. The aim of this study was to investigate potential biomarkers of cartilage metabolism in OA using a targeted multiplex approach by single reaction monitoring. Intact looking cartilage of femoral heads from patients with OA (n = 9) or femoral neck fractures (n = 12) was examined. Variations and relative quantifications of 35 selected extracellular matrix (ECM) proteins were analyzed using nano-LC coupled to tandem mass spectrometry. Our study showed statistically significantly increased levels of asporin (ASPN), mimecan (MIME), matrilin-3 (MATN3), cartilage intermediate layer protein 2 (CILP-2), collagen VI, collagen II, and collagen III N-propeptide in OA cartilage compared with non-OA cartilage. The other proteins in the protein panel did not appear to be different between the two groups. In conclusion, we identified a number of cartilage matrix proteins which may represent early molecular changes in the OA process and may have potential to predict the development of OA. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The aim of this study was to investigate the local production of proinflammatory cytokines, pain-related sensory innervation of dorsal-root ganglia (DRG), and spinal changes in a rat model of induced hip osteoarthritis (OA). Seventy-five Sprague-Dawley rats were used, including 25 controls and 50 injected into the right hip joints (sham group, injected with 25 µl of sterile saline: N = 25; and monosodium iodoacetate (MIA) group, injected with 25 µl of sterile saline with 2 mg of MIA: N = 25). We measured the local production of TNF-α, immunoreactive (-ir) neurons for calcitonin gene-related peptide (CGRP), and growth associated protein-43 (GAP-43) in DRG, and immunoreactive neurons for ionized-calcium-binding adaptor molecule-1 (Iba-1) in the dorsal horn of spinal cord, on post-induction days 7, 14, 28, 42, and 56 (N = 5 rats/group/time point). For post-induction days 7-42, the MIA group presented significantly elevated concentrations of TNF-α than the other groups (p < 0.01), and a higher expression of CGRP-ir in FG-labeled DRG neurons than the sham group (p < 0.01). MIA rats also presented significantly more FG-labeled GAP-43-ir DRG neurons than the sham group on post-induction days 28, 42, and 56 (p < 0.05), and a significantly higher number of Iba-1-ir microglia in the ipsilateral dorsal horn than the other groups, on post-induction days 28, 42, and 56. The results suggest that in rat models, pain-related pathologies due to MIA-induced hip OA, originate from inflammation caused by cytokines, which leads to progressive, chronic neuronal damage that may cause neuropathic pain. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2978-2986, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Regional intraarticular delivery of local anesthetics is effective in treating postoperative pain following total knee or hip replacement. Recent research efforts have been only partially successful in achieving sustained release of the analgesic agent, in part due to limited understanding of the biological environment into which these formulations are administered. This study aimed to detail the composition and properties of postoperative periarticular fluid (PO-PAF). PO-PAF was collected from 8 patients, and the composition and physicochemical properties were determined. A number of components were identified which are lacking from phosphate buffered saline (PBS) or other synthetic media. The differences in composition led to variation in the physicochemical properties of PO-PAF compared with PBS. Notably, significantly lower surface tension (p <0.05) and higher buffer capacity (p <0.05) were observed in the biological fluid. We demonstrated that the solubility of lidocaine is almost double in PO-PAF compared to PBS (p <0.05) and that lidocaine release from a poloxamer gelling system occurred faster into PO-PAF under both sink and nonsink conditions. Collectively, these data indicate PBS is inappropriate for the in vitro evaluation of intraarticular drug delivery systems. The presented data describe that PO-PAF and will support the future development of biorelevant media to ultimately improve in vivo-in vitro correlation., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Introduction: Osteoarthritis (OA) is the most common degenerative joint disease and one of the major causes of disability worldwide. It is a multifactorial disorder with a significant genetic component. The heritability of OA has been estimated to be 60% for hip OA and 39% for knee OA. Genetic factors behind OA are still largely unknown. Studying families with strong history of OA, facilitates examining the co-segregation of genetic variation and OA. The aim of this study was to identify new, rare genetic factors and novel candidate genes for OA., Methods: Eight patients from three Finnish families with hip and knee OA were studied using whole exome sequencing. We focused on rare exonic variants with predicted pathogenicity and variants located in active promoter or strong enhancer regions. Expression of identified candidate genes were studied in bone and cartilage tissues and the observed variants were investigated using bioinformatic analyses., Results: Two rare variants co-segregated with OA in two families. In Family 8 a missense variant (c.628C>G, p.Arg210Gly) was observed in the OLIG3 gene that encodes a transcription factor known to be associated with rheumatoid arthritis and inflammatory polyarthritis. The Arg210Gly variant was estimated to be pathogenic by Polyphen-2 and Mutation taster and the locus is conserved among mammals. In Family 12 the observed variant (c.-127G>T) was located in the transcription start site of the FIP1L1 gene. FIP1L1 participates in the regulation of polyadenylation. The c.-127G>T is located in the transcription start site and may alter the DNA-binding of transcription factors. Both, OLIG3 and FIP1L1 were observed in human bone and cartilage., Conclusion: The identified variants revealed novel candidate genes for OA. OLIG3 and FIP1L1 have specific roles in transcription and may effect expression of other genes. Identified variants in these genes may thus have a role in the regulatory events leading to OA., Competing Interests: Leena Ala-Kokko is employed by The Connective Tissue Gene Tests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To identify molecular differences between chondrocytes from osteophytic and articular cartilage tissue from OA patients., Methods: We investigated genes and pathways by combining genome-wide DNA methylation, RNA sequencing and quantitative proteomics in isolated primary chondrocytes from the cartilaginous layer of osteophytes and matched areas of low- and high-grade articular cartilage across nine patients with OA undergoing hip replacement surgery., Results: Chondrocytes from osteophytic cartilage showed widespread differences to low-grade articular cartilage chondrocytes. These differences were similar to, but more pronounced than, differences between chondrocytes from osteophytic and high-grade articular cartilage, and more pronounced than differences between high- and low-grade articular cartilage. We identified 56 genes with significant differences between osteophytic chondrocytes and low-grade articular cartilage chondrocytes on all three omics levels. Several of these genes have known roles in OA, including ALDH1A2 and cartilage oligomeric matrix protein, which have functional genetic variants associated with OA from genome-wide association studies. An integrative gene ontology enrichment analysis showed that differences between osteophytic and low-grade articular cartilage chondrocytes are associated with extracellular matrix organization, skeletal system development, platelet aggregation and regulation of ERK1 and ERK2 cascade., Conclusion: We present a first comprehensive view of the molecular landscape of chondrocytes from osteophytic cartilage as compared with articular cartilage chondrocytes from the same joints in OA. We found robust changes at genes relevant to chondrocyte function, providing insight into biological processes involved in osteophyte development and thus OA progression.

Objective: To date, exhaustive gene expression analyses of chondrocytes in hip osteoarthritis (OA) have yielded specific gene expression patterns. No study has reported on the exhaustive transcriptome of secondary hip OA based on acetabular dysplasia in a Japanese population, while previous reports have focused on primary or idiopathic hip OA in Caucasian populations. This study aims to search for specific gene expression patterns of secondary hip OA chondrocytes by transcriptome analysis., Design: Human articular cartilage was obtained from femoral heads following hemiarthroplasty for femoral neck fracture (N = 8; non-OA) and total hip arthroplasty for secondary hip OA (N = 12). Total RNA was extracted from the articular cartilage and submitted for microarray analysis. The obtained data were used to perform gene expression analysis, GO enrichment analysis and pathway analysis and were compared with data from primary hip OA in Caucasian populations in the literature., Results: We identified 888 upregulated (fold change: FC ≥ 2) and 732 downregulated (FC ≤ 0.5) genes in hip OA versus non-OA chondrocytes, respectively. Only 10% of upregulated genes were common between the secondary and primary OA. The newly found genes prominently overexpressed in the secondary hip OA chondrocytes were DPT, IGFBP7, and KLF2. Pathway analysis revealed extracellular matrix (ECM)-receptor interaction as an OA-related pathway, which was similar to previous reports in primary hip OA., Conclusions: This is the first study to report the genome-wide transcriptome of secondary hip OA chondrocytes and demonstrates new potential OA-related genes. Gene expression patterns were different between secondary and primary hip OA, although the results of pathway and functional analysis were similar., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Synovial membrane inflammation is the most commonly presenting finding during hip arthroscopy and may have a role in the pathomechanism of hip osteoarthritis (OA). The aim of this study was to determine the relationship between synovial cytokine levels and progression of OA after hip arthroscopy., Methods: We prospectively examined 20 patients (20 hips) who underwent arthroscopic hip surgery. For all patients, radiographs and severity of pain were evaluated preoperatively. During arthroscopy, we harvested a sample of the synovial membrane and determined the levels of six typical inflammatory cytokines with real-time polymerase chain reaction. We compared the levels of these cytokines in patients who showed OA progression and non-progression after hip arthroscopy., Results: Although the average age of patients who showed OA progression postoperatively tended to be higher, there were no significant differences in characteristics involving clinical assessment between patients who showed OA progression and those who showed non-progression. Intraoperative tumour necrosis factor α (TNFα) expression was significantly higher in patients who showed OA progression postoperatively ( p = 0.042)., Conclusions: Elevation of TNFα level might be a predictor of OA progression after hip arthroscopy.

Background: Inflammation is associated with the onset and progression of osteoarthritis in multiple joints. It is well known that mechanical properties differ between different joints, however, it remains unknown if the inflammatory process is similar/distinct in patients with hip vs. knee OA. Without complete understanding of the role of any specific cytokine in the inflammatory process, understanding the 'profile' of inflammation in a given patient population is an essential starting point. The aim of this study was to identify serum cytokine profiles in hip Osteoarthritis (OA), and investigate the association between cytokine concentrations and clinical measurements within this patient population and compare these findings to knee OA and healthy control cohorts., Methods: In total, 250 serum samples (100 knee OA, 50 hip OA and 100 control) and 37 synovial fluid samples (8 knee OA, 14 hip OA and 15 control) were analyzed using a multiplex ELISA based approach. Synovial biopsies were also obtained and examined for specific cytokines. Pain, physical function and activity within the hip OA cohort were examined using the HOOS, SF-36, HHS and UCLA outcome measures., Results: The three cohorts showed distinct serum cytokine profiles. EGF, FGF2, MCP3, MIP1α, and IL8 were differentially expressed between hip and knee OA cohorts; while FGF2, GRO, IL8, MCP1, and VEGF were differentially expressed between hip OA and control cohorts. Eotaxin, GRO, MCP1, MIP1β, VEGF were differentially expressed between knee OA and control cohorts. EGF, IL8, MCP1, MIP1β were differentially expressed in synovial fluid from a sub-set of patients from each cohort. Specifically within the hip OA cohort, IL-6, MDC and IP10 were associated with pain and were also found to be present in synovial fluid and synovial membrane (except IL-6) of patients with hip OA., Conclusion: OA may include different inflammatory subtypes according to affected joints and distinct inflammatory processes may drive OA in these joints. IL6, MDC and IP10 are associated with hip OA pain and these proteins may be able to provide additional information regarding pain in hip OA patients.

Background: Oxidative stress constitutes an important risk factor for tissue/cell damage and is involved in the occurrence and progression of Osteoarthritis (OA)., Objective: The aim of this study was to evaluate the concentration of Malondialdehyde (MDA) in Synovial Fluid (SF) and blood as well as the activity of serum and SF paraoxonase (PON1) of patients with OA. Our study aimed to assess local and systemic responses to oxidative stress., Methods: The study included 43 subjects with OA qualified to total joint replacement. The control group consisted of 58 subjects with no musculoskeletal disorders. The malondialdehyde level were measured in venous blood plasma, erythrocytes (MDAe) and Synovial Fluid (SF) while PON1 activities were estimated in serum and SF., Results: No differences in MDA concentrations in erythrocytes and blood plasma between healthy subjects and OA patients were observed. The significant higher level of MDA in SF compared with blood serum was seen in both genders (in woman about 46.2%, in men - 75.0%) and in both assessed joints (in hip about 53.8%, in knee - 115.9%). Total protein concentration and PON1 activity in serum were significantly higher in OA patients (about 14.6% and 87.9% respectively). The systemic response to osteoarthritis (serum PON1 activity) was higher about 33.6% in men than women and not dependent on affected joint., Conclusion: The changes observed in osteoarthritic SF show that the process of antioxidant enzymatic defence is intensified locally, not systemically. The lipid hydroperoxides elimination may lead to restore joints homeostasis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: The objective of the work to determine the diagnostic role of the three phase bone scintigraphy (3 F BS) in the early prediction of paraendoprosthetic complications of the hip and knee joints of the participants in clean up workers of Chornobyl accident., Material and Methods: The 3 F BS method were investigated the radionuclide kinetic parameters of the inclusion and distribution of radiopharmaceuticals (RF) in damaged joints in the 75 male clean up workers., Results: It was established that calculating the quantitative indices of kinetics of the drug at various stages of the 3 F BS allowed to determine statistically significant differences in metabolic changes in focal lesions in articular structures. Thus, the differential diagnostic capabilities of the radionuclide method of examination of patients with arthroplasty of the hip and knee joints are elevated., Conclusions: The kinetics of osteotropic RF in the foci of fixing the damaged hip and knee joints in the infectious and inflammatory processes is characterized by the predominance of retention and specific accumulation of the drug in the early static phase and the delayed static phase of the 3 F BS compared with the centers of fixation of RF in deforming osteoarthroses, which correlates with the differences in destructive reparative processes in them., (M. M. Tkachenko, P. O. Korol.)

Osteoarthritis (OA) is a degenerative disease characterized by the destruction of cartilage. The greatest risk factors for the development of OA include age and obesity. Recent studies suggest the role of inflammation in the pathogenesis of OA. The two most common locations for OA to occur are in the knee and hip joints. The knee joint experiences more mechanical stress, cartilage degeneration, and inflammation than the hip joint. This could contribute to the increased incidence of OA in the knee joint. Damage-associated molecular patterns (DAMPs), including high-mobility group box-1, receptor for advanced glycation end products, and alarmins (S100A8 and S100A9), are released in the joint in response to stress-mediated chondrocyte and cartilage damage. This facilitates increased cartilage degradation and inflammation in the joint. Studies have documented the role of DAMPs in the pathogenesis of OA; however, the comparison of DAMPs and its influence on OA has not been discussed. In this study, we compared the DAMPs between OA knee and hip joints and found a significant difference in the levels of DAMPs expressed in the knee joint compared to the hip joint. The increased levels of DAMPs suggest a difference in the underlying pathogenesis of OA in the knee and the hip and highlights DAMPs as potential therapeutic targets for OA in the future.

Background: Due to degradation and metal dissolution during articulation of metal joint replacements the chemical periprosthetic environment may change. The aim was to establish whether metal replacements cause the local changes in pH and elevated metal concentrations., Methods: pH was measured on samples from 167 patients: native hip and knee osteoarthritic joints, joints with hip and knee replacements revised for aseptic or septic reasons. pH of synovial fluid and periprosthetic tissue was measured perioperatively using a microelectrode and pH indicator papers for removed metal components. Metal concentrations were measured in 21 samples using inductively coupled plasma mass spectrometry., Results: The mean pH value of synovial fluid at native osteoarthritic joints (n = 101) was 7.78 ± 0.38. The mean pH value of synovial fluid at revision aseptic operation (n = 58) was 7.60 ± 0.31, with statistically significant difference (p = 0.002) compared to native osteoarthritic joints. The mean pH value of synovial fluid at revision septic operation (n = 8) was 7.55 ± 0.25, with statistically significant difference (p = 0.038) compared to native osteoarthritic joints. Measurements in tissue and at stems were not reliable. In the majority of samples taken at revision increased levels of cobalt and chromium were measured., Conclusion: A small but statistically significant difference was observed in the pH of synovial fluid between natural joints with degenerative diseases and joints treated with metal replacements. Based on the increased metal levels we expected the value of pH to be lower, but the influence of metal ions is counteracted by the buffering capacity of human body. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2507-2515, 2017., (© 2016 Wiley Periodicals, Inc.)