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Osteoarthritis (OA) is no longer regarded as a simple wear-and-tear problem of articular cartilage. Instead, OA is a whole joint disorder involving both cartilaginous and non-cartilaginous tissues such as subchondral bone and synovium. Among them, subchondral bone undergoes constant remodeling in response to the changes of mechanical environment. Current understanding of subchondral bone disturbance in OA is limited to its link with an altered local mechanical loading as a result of ligament or meniscus injury. Very recently, hypertension, the most common vascular morbidity, has been emerged as an independent risk factor of OA. It might suggest a plausible role of systemic hemodynamic mechanical stress in subchondral bone remodeling and the pathogenesis of OA. However, their relationship remains not fully understood. Based on our preliminary clinical observation on the association of hemodynamic parameters with subchondral bone mass and microstructure in late-stage knee OA patients, we formulate a vascular etiology hypothesis of OA from a mechanobiology perspective. Noteworthily, hemodynamic stress associated with subchondral bone mineral density; yet compressive mechanical loading does not. Furthermore, hemodynamic parameters positively correlated with subchondral plate-like trabecular bone volume but negatively associated with rod-like trabecular bone volume. In contrast, compressive mechanical loading tends to increase both plate-like and rod-like trabecular bone volume. Taken together, it warrants further investigations into the distinct role of hemodynamic or compressive stress in shaping subchondral bone in the pathophysiology of OA. The Translational potential of this article: This work provides a new insight, from the angle of biomechanics, into the emerging role of vascular pathologies, such as hypertension, in the pathogenesis of OA. It might open up a new avenue for the development of a mechanism-based discovery of novel diagnostics and therapeutics.

Summary: Objective: To investigate the mitigate efficacy of Chinese medicine Lingzhi (LZ) and San-Miao-San (SMS) combined with hyaluronic acid (HA)-gel in attenuating cartilage degeneration in traumatic osteoarthritis (OA). Methods: The standardized surgery of anterior cruciate ligament transection (ACLT) was made from the medial compartment of right hind limbs of 8-week-old female SD rats and resulted in a traumatic OA. Rats (n ​= ​5/group) were treated once intra-articular injection of 50 ​μl HA-gel, 50 ​μl HA-gel+50 ​μg LZ-SMS, 50 ​μl of saline+50 ​μg LZ-SMS and null (ACLT group) respectively, except sham group. Limbs were harvested for μCT scan and histopathological staining 3-month post-treatment. Inflammatory cytokines from plasma and synovial fluid were detected using Immunology Multiplex Assay kit. The putative targets of active compounds in LZ-SMS and known therapeutic targets for OA were combined to construct protein–protein interaction network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was adopted to predict the potential targets and signaling pathway of LZ-SMS in OA through the tool of DAVID Bioinformatics. Results: In vivo, HA-gel ​+ ​LZ-SMS treatment resulted in a higher volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and HC/Sum (total volume of cartilage), compared to ACLT and HA-gel groups. In addition, histological results showed the elevated cartilage matrix, chondrogenic and osteoblastic signals in HA-gel ​+ ​LZ-SMS treatment. Treatment also significantly altered subchondral bone (SCB) structure including an increase in BV/TV, Tb.Th, BMD, Conn.Dn, Tb.N, and DA, as well as a significant decrease in Tb.Sp and Po(tot), which implied a protective effect on maintaining the stabilization of tibial SCB microstructure. Furthermore, there was also a down-regulated inflammatory cytokines and upregulated anti-inflammatory cytokine IL-10 in HA+LZ-SMS group. Finally, 64 shared targets from 37 active compounds in LZ-SMS related to the core genes for the development of OA. LZ-SMS has a putative role in regulating inflammatory circumstance through influencing the MAPK signaling pathway. Conclusion: Our study elucidated a protective effect of HA-gel ​+ ​LZ-SMS in mitigating cartilage degradation and putative interaction with targets and signaling pathway for the development of traumatic OA. The translational potential of this article: Our results provide a biological rationale for the use of LZ-SMS as a potential candidate for OA treatment.

Objective: This study aimed to investigate the abnormal subchondral trabecular bone (STB) remodeling in knee osteoarthritis (OA) under the influence of knee alignment [hip-knee-ankle (HKA) angle].Design: Forty-one patients with knee OA underwent radiographic examination before total knee arthroplasty (TKA) for the measurement of HKA angle. Tibial plateau specimens obtained during TKA were used for histomorphometric analyses to assess STB remodeling and cartilage degradation. Tartrate-resistant acidic phosphatase (TRAP) staining was used to test osteoclast activity. Osterix, osteocalcin, and sclerostin expression in the STB were determined using immunohistochemistry.Results: The interaction between HKA angle and side (medial vs lateral of tibial plateau) was the main significant influence factor for STB remodeling and microstructure. The STB with the deviation of the knee alignment was accompanied by obvious abnormal bone remodeling and microstructural sclerosis. Bone volume fraction (BV/TV) was the only significant influence factor for OARSI score, the larger the BV/TV of STB, the higher the OARSI score of cartilage. Moreover, the tibial plateau affected by alignment had more TRAP + osteoclasts, Osterix + osteoprogenitors, and osteocalcin + osteoblasts and fewer sclerostin + osteocytes.Conclusions: The variation of tibial plateau STB remodeling activity and microstructure was associated with HKA angle and cartilage degradation. Knee malalignment may cause abnormal STB remodeling and microstructural sclerosis, which may potentially affect load stress transmission from the cartilage to the STB, thus resulting in accelerated knee OA progression. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the relationship between the micro structural properties of the subchondral trabecular bone (STB) and the macro mechanical properties of the articular cartilage (AC) in patients with osteoporotic (OP) and osteopenic (OPE) fractures. Sixteen femoral head samples (OP;OPE, n = 8 each) were obtained from female patients who underwent hip hemiarthroplasty. STB and AC specimens were harvested from those heads. Bone specimens were scanned using µ-CT to determine the micro structural properties. In-situ nondestructive compressive tests were performed for the cartilages to obtain elastic properties. The finite element technique was implemented on STB models created from µ-CT data to compute apparent elastic modulus. In addition, dynamic cyclic destructive tests were performed on STB and AC specimens to assess failure cycles. The results demonstrated that STB specimens in OPE group have more interconnected structure and higher cyclic dynamic strength than those in OP group. Furthermore, bone mineral density, failure cycle, and trabecular number of STB were positively correlated with the cartilage failure cycle, which indicates that STB alteration may affect the macroscopic mechanical properties of AC. The findings suggest that STB loss correlates with a decrease in cartilage strength and that improving of bone quality may prevent cartilage weakness. [ABSTRACT FROM AUTHOR]

Abstract Background Knee osteoarthritis (OA) is a common disabling disease involving the entire joint tissue, and its onset and progression are affected by many factors. However, the current number of studies investigating the relationship between subchondral trabecular bone (STB), knee alignment, and OA severity is limited. We aimed to investigate the variation in tibial plateau STB microarchitecture in end-stage knee OA patients and their association with knee alignment (hip-knee-ankle, HKA, angle) and OA severity. Methods Seventy-one knee OA patients scheduled for total knee arthroplasty (TKA) underwent preoperative radiography to measure the HKA angle and Kellgren-Lawrence grade. Tibial plateaus collected from TKA were scanned using micro-computed tomography to analyze the STB microarchitecture. Histological sections were used to assess cartilage degeneration (OARSI score). Correlations between the HKA angle, OA severity (OARSI score, Kellgren-Lawrence grade), and STB microarchitecture were evaluated. Differences in STB microstructural parameters between varus and valgus alignment groups based on the HKA angle were examined. Results The HKA angle was significantly correlated with all STB microarchitecture parameters (p

Objective: Developmental dysplasia of the hip (DDH) is recognized as a frequent cause of secondary osteoarthritis (OA). The purpose in this study was to compare structural and biomechanical properties of subchondral trabecular bone ​and its relationship with cartilage damage between patients with DDH and patients with primary hip OA. Methods: Forty-three femoral head specimens obtained from patients who underwent total hip arthroplasty [DDH, n ​= ​17; primary OA, n ​= ​16; and normal control (NC), n ​= ​10] were scanned by microcomputed tomography and analyzed by individual trabecula segmentation to obtain the microstructural types of subchondral trabecular bone. The biomechanical properties were analyzed by micro–finite element analysis, and cartilage damage was evaluated by histology. The linear regression analysis was used to indicate the association between microstructures, biomechanical property, and articular cartilage. Results: The DDH group showed the lowest total bone volume fractions (BV/TV) and plate BV/TV in the three groups (p ​

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Visualization and quantification of bone microarchitecture in the human knee allows gaining insight into normal bone structure, and into the structural changes occurring in the onset and progression of bone diseases such as osteoporosis and osteoarthritis. However, current imaging modalities have limitations in capturing the intricacies of bone microarchitecture. Photon counting computed tomography (PCCT) is a promising imaging modality that presents high-resolution three-dimensional visualization of bone with a large field of view. However, the potential of PCCT in assessing trabecular microstructure has not been investigated yet. Therefore, this study aimed to evaluate the accuracy of PCCT in quantifying bone microstructure and bone mechanics in the knee. Five human cadaveric knees were scanned ex vivo using a PCCT scanner (Naetom alpha, Siemens, Germany) with an in-plane resolution of 146.5 μm and slice thickness of 100 μm. To assess accuracy, the specimens were also scanned with a high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT II, Scanco Medical, Switzerland) with a nominal isotropic voxel size of 60.7 μm as well as with micro-computed tomography (micro-CT; TESCAN UniTOM XL, Czech Republic) with a nominal isotropic voxel size of 25 μm which can be considered gold standards for in vivo and ex vivo scanning, respectively. The thickness and porosity of the subchondral bone and the microstructure of the underlying trabecular bone were assessed in the load bearing regions of the proximal tibia and distal femur. The apparent Young's modulus was determined by micro-finite element (μFE) analysis of subchondral trabecular bone (STB) in the load bearing regions of the proximal tibia using PCCT, HR-pQCT and micro-CT images. The correlation between PCCT measurements and micro-CT and HR-pQCT, respectively, was calculated. The coefficients of determination (R2) between PCCT and micro-CT based parameters, ranged from 0.69 to 0.87. The coefficients of determination between PCCT and HR-pQCT were slightly higher and ranged from 0.71 to 0.91. Apparent Young's modulus, assessed by μFE analysis of PCCT images, correlated well with that of micro-CT (R2 = 0.80, mean relative difference = 19 %). However, PCCT overestimated the apparent Young's modulus by 47 %, but the correlation (R2 = 0.84) remained strong when compared to HR-pQCT. The results of this study suggest that PCCT can be used to quantify bone microstructure in the knee. • Bone microstructure can be quantified using photon counting CT (PCCT). • PCCT-based bone microarchitecture was validated by micro-CT and HR-pQCT. • PCCT-based quantification of bone stiffness was validated by micro-CT and HR-pQCT. • PCCT is a novel technique for future in vivo microstructural imaging. [ABSTRACT FROM AUTHOR]

According to the Chinese medicine, magnoflorine exerted significant anti-inflammatory effects and potentially promoted synthesis of proteoglycans in chondrocytes to reverse the progression of rheumatoid arthritis. However, the latent beneficial effect of magnoflorine for the treatment of traumatic osteoarthritis (OA) is still unknown. Therefore, we aim to demonstrate the efficacy of magnoflorine combined with HA-gel in attenuating cartilage degeneration in anterior cruciate ligament transection (ACLT) induced OA rat model. We found that the histological results showed the elevated cartilage matrix, chondrogenic signals and chondroprogenitor cells in HA-gel + magnoflorine treatment. HA-gel + magnoflorine treatment resulted in a decreased modified Mankin’s score, and a higher volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and HC/Sum (whole cartilage), compared to ACLT and HA-gel groups. Furthermore, both the volume ratios of HC/Sum and HC/CC were negatively correlated with modified Mankin’s scores. Finally, HA-gel + magnoflorine could significantly increase the BV/TV, Tb.Th, and decrease the Tb.Pf, Po(tot), Conn.Dn and Tb.Sp. In vitro, 50 μg/ml magnoflorine treatment could significantly increase the viability, S-phase, migration rate and chondrogenesis of chondroprogenitor cells. There were significant downregulations of MAPK/NF-κB signaling, and upregulations of chondrogenic signals in 50 μg/ml magnoflorine treatment. There were significant downregulations of proinflammatory cytokines and upregulation of IL-10 in HA-gel + magnoflorine treated group. Therefore, our study elucidated a protective effect of HA-gel + magnoflorine on attenuating cartilage degradation and maintaining SCB stabilization in ACLT induced OA.

Introduction: Bone marrow lesions (BMLs) are frequently identified by MRI in the subchondral bone in knee osteoarthritis (KOA). BMLs are known to be closely associated with joint pain, loss of the cartilage and structural changes in the subchondral trabecular bone (SCTB). Despite this, understanding of the nature of BMLs at the trabecular tissue level is incomplete. Thus, we used Raman microspectroscopy to examine the biochemical properties of SCTB from KOA patients with presence or absence of BMLs (OA-BML, OA No-BML; respectively), in comparison with age-matched cadaveric non-symptomatic controls (Non-OA CTL). Methods: Tibial plateau (TP) specimens were collected from 19 KOA arthroplasty patients (6-Male, 13-Female; aged 56–74 years). BMLs were identified ex-vivo by MRI, using PDFS- and T1-weighted sequences. The KOA specimens were then categorized into an OA-BML group (n = 12; containing a BML within the medial condyle only) and an OA No-BML group (n = 7; with no BMLs identified in the TP). The control (CTL) group consisted of Non-OA cadaveric TP samples with no BMLs and no macroscopic or microscopic evidence of OA-related changes (n = 8; 5-Male, 3-Female; aged 44–80 years). Confocal Raman microspectroscopy, with high spatial resolution, was used to quantify the biochemical properties of SCTB tissue of both the medial and the lateral condyle in each group. Results: The ratios of peak intensity and integrated area of bone matrix mineral (Phosphate (v1), Phosphate (v2) and Phosphate (v4)), to surrogates of the organic phase of bone matrix (Amide I, Proline and Amide III), were calculated. Within the medial compartment, the mineral:organic matrix ratios were significantly lower for OA-BML, compared to Non-OA CTL. These ratios were also significantly lower for the OA-BML medial compartment, compared to the OA-BML lateral compartment. There were no group or compartmental differences for Carbonate:Phosphate (v1, v2 and v4), Amide III (α-helix):Amide III (random-coil), Hydroxyproline:Proline, or Crystallinity. Conclusion: As measured by Raman microspectroscopy, SCTB tissue in BML zones in KOA is significantly less mineralized than the corresponding zones in individuals without OA. These data are consistent with those obtained using other methods (e.g. Fourier transform infrared spectroscopy; FTIR) and with the increased rate of bone remodeling observed in BML zones. Reduced mineralization may change the biomechanical properties of the trabecular bone in BMLs and the mechanical interaction between subchondral bone and its overlying cartilage, with potential implications for the development and progression of OA.

Objectives: The objective was to estimate the impact of the meniscus on cartilage and subchondral bone in knee osteoarthritis (OA). Methods: In a sample of 46 knee specimens (26 females), 13 (7 females) were classified as OA according to the Kellgren-Lawrence classification. Outerbridge and meniscal grading were performed. Using micro-computed tomography images, we analyzed the cartilage thickness, subchondral plate thickness and micro-architecture of trabecular subchondral bone at different depths and in two different locations of the medial tibial plateau: one peripheral (PER) covered by the meniscus and one central (CENT) uncovered by the meniscus. Results: Uncoverage by the meniscus was associated with bone sclerosis, defined as higher bone volume to total volume (BV/TV), higher trabecular number, thicker trabeculae with lower spacing, and anisotropy and a more plate-like architecture. The protective effect of meniscal coverage was observed in the uppermost 5 to 6 mm of the subchondral bone. As compared with normal knees, knees with OA showed significantly higher bone sclerosis (P

Abstract Objective To investigate efficacy of Chinese medicine magnoflorine combined with hyaluronic acid (HA)-gel in promoting subchondral bone (SCB) regeneration and attenuating cartilage degeneration in early osteoarthritis (OA). Methods MC3T3-E1 under magnoflorine treatment was assayed by XTT to determine cell viability. Cell proliferation was reflected through cell cycle. Osteoblast mineralization was stained by Alizarin Red. Standardized bone canal of 1 mm in diameter and 4 mm in depth was made on tibial medial plateau of 4-month-old Dunkin-Hartley spontaneous knee OA guinea pigs. Guinea pigs (n = 5/group) were treated once intra-bone canal injection of 2 μl HA-gel, 2 μl HA-gel+50 ng magnoflorine and null (Defect) respectively, except sham group. The left hind limbs were harvested for μCT scan and histopathological staining 2-month post-surgery. Results 25 μg/ml magnoflorine treatment significantly increased cell viability, S-phase and mineralization of MC3T3-E1 cells. In vivo, HA-gel + magnoflorine treatment significantly altered SCB microstructure; changes included increase in bone volume fraction (BV/TV), trabecular number (Tb.N), connectivity density (Conn.Dn), and decrease in degree of anisotropy (DA), which implied trabecular bone regeneration. Treatment also resulted in a decrease in modified Mankin's scores, and an increase in volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and fractal dimension (FD, roughness indicator of osteochondral conjunction), compared to Defect and HA groups. Furthermore, FD was positively associated with volume ratio of HC/CC and negatively associated with modified Mankin's scores. Finally, histological results showed that due to a faster regeneration of SCB with the HA-gel + magnoflorine treatment, the reduction of cartilage matrix and the decreased expression of chondrogenic signals were attenuated. Conclusion Our study elucidated the potential benefits of HA-gel + magnoflorine in promoting SCB regeneration and revealed a protective effect of stimulating recovery of the SCB integrity on attenuating cartilage degradation to prevent OA progression. Highlights • Recovery subchondral bone integrity is pivotal to attenuate cartilage degeneration. • Magnoflorine might directly stimulate osteoblast differentiate to calcified osteoid. • Magnoflorine prevents OA progression by preventing subchondral bone loss. [ABSTRACT FROM AUTHOR]

Objective: To study, in end-stage knee osteoarthritis (OA) patients, relationships between indices of in vivo dynamic knee joint loads obtained pre-operatively using gait analysis, static knee alignment, and the subchondral trabecular bone (STB) microarchitecture of their excised tibial plateau quantified with 3D micro-CT.Design: Twenty-five knee OA patients scheduled for total knee arthroplasty underwent pre-operative gait analysis. Mechanical axis deviation (MAD) was determined radiographically. Following surgery, excised tibial plateaus were micro-CT-scanned and STB microarchitecture analysed in four subregions (anteromedial, posteromedial, anterolateral, posterolateral). Regional differences in STB microarchitecture and relationships between joint loading and microarchitecture were examined.Results: STB microarchitecture differed among subregions (P < 0.001), anteromedially exhibiting highest bone volume fraction (BV/TV) and lowest structure model index (SMI). Anteromedial BV/TV and SMI correlated strongest with the peak external rotation moment (ERM; r = -0.74, r = 0.67, P < 0.01), despite ERM being the lowest (by factor of 10) of the moments considered, with majority of ERM measures below accuracy thresholds; medial-to-lateral BV/TV ratios correlated with ERM, MAD, knee adduction moment (KAM) and internal rotation moment (|r|-range: 0.54-0.74). When controlling for walking speed, KAM and MAD, the ERM explained additional 11-30% of the variations in anteromedial BV/TV and medial-to-lateral BV/TV ratio (R2 = 0.59, R2 = 0.69, P < 0.01).Conclusions: This preliminary study suggests significant associations between tibial plateau STB microarchitecture and knee joint loading indices in end-stage knee OA patients. Particularly, anteromedial BV/TV correlates strongest with ERM, whereas medial-to-lateral BV/TV ratio correlates strongest with indicators of medial-to-lateral joint loading (MAD, KAM) and rotational moments. However, associations with ERM should be interpreted with caution. [ABSTRACT FROM AUTHOR]

ABSTRACT: Developing effective treatment for osteoarthritis (OA), a prevalent and disabling disease, has remained a challenge, primarily because of limited understanding of its pathogenesis and late diagnosis. In the subchondral bone, rapid bone loss after traumatic injuries and bone sclerosis at the advanced stage of OA are well‐recognized hallmarks of the disease. Recent studies have further demonstrated the crucial contribution of subchondral bone in the development of OA. However, the microstructural basis of these bone changes has not been examined thoroughly, and the paradox of how abnormal resorption can eventually lead to bone sclerosis remains unanswered. By applying a novel microstructural analysis technique, individual trabecula segmentation (ITS), to micro‐computed tomography (μCT) images of human OA knees, we have identified a drastic loss of rod‐like trabeculae and thickening of plate‐like trabeculae that persisted in all regions of the tibial plateau, underneath both severely damaged and still intact cartilage. The simultaneous reduction in trabecular rods and thickening of trabecular plates provide important insights to the dynamic and paradoxical subchondral bone changes observed in OA. Furthermore, using an established guinea pig model of spontaneous OA, we discovered similar trabecular rod loss and plate thickening that preceded cartilage degradation. Thus, our study suggests that rod‐and‐plate microstructural changes in the subchondral trabecular bone may play an important role in the development of OA and that advanced microstructural analysis techniques such as ITS are necessary in detecting these early but subtle changes. With emerging high‐resolution skeletal imaging modalities such as the high‐resolution peripheral quantitative computed tomography (HR‐pQCT), trabecular rod loss identified by ITS could potentially be used as a marker in assessing the progression of OA in future longitudinal studies or clinical diagnosis. © 2017 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objective: The pathogenesis of osteoarthritis (OA) is not fully understood, but bone changes are suggested to be important. Bone turnover and bone volume (BV) in human hip OA were investigated in relation to the overlying cartilage degeneration using design-based stereological estimators.Materials and Methods: Femoral heads were obtained from 25 end-stage OA patients and 24 controls (CTL). Design-based stereological methods were used for sampling and quantification to obtain absolute estimates of volume and surface in the central trabecular and the subarticular bone region. The subarticular bone was further subdivided into regions according to the OARSI-score of the overlying articular cartilage in which erosion and osteoid surfaces were estimated.Results: In the subarticular region, bone volume (BV/TV) was 15.0% higher in OA patients compared to CTL; The fraction of erosive (ES/BS) and osteoid surfaces (OS/BS) were 56.2% and 72.8% higher in OA compared to CTL. In subarticular regions with none to mild cartilage degeneration (OARSI grade 0-2), ES/BS and OS/BS were 48.6% and 59.9% higher in OA compared to CTL, whereas BV/TV did not differ between OA and CTL.Conclusion: In human end-stage hip OA, BV and bone turnover correlate with the degree of local cartilage degeneration. Subarticular bone sclerosis was only present in regions corresponding to end-stage OA. However, in regions with only none to mild cartilage degeneration the underlying bone had significantly higher turnover in OA patients compared to the control group, suggesting that high bone turnover may contribute to the early pathogenesis of OA. [ABSTRACT FROM AUTHOR]

Summary: Objective: Explore whether osteoporosis (OP) in humans influences the morphological status of the articular cartilage and the subchondral bone. Explore the relationship between the macroscopic aspect of the articular surface and the rate of microscopic changes of both the cartilage and the subchondral bone in OP and osteoarthritis (OA). Methods: Femoral heads after total hip replacement were obtained from patients with OP or hip OA (OP, n = 56; OA, n = 12). Cartilage degeneration was assessed using the Mankin grading system whereas subchondral bone was evaluated using histomorphometry and Micro-computed Tomography (μCT) scanning system. Thickness of the cartilage layers and subchondral cortical bone (SCB) was measured. Results: Samples with higher total Mankin score have significantly reduced cartilage thickness. Mankin score differed between all OP specimens. In OP samples with lower Mankin scores the thickness of SCB shows a trend of an increase caused by increased levels of bone remodeling. In OP samples with higher Mankin scores we observed thinning of SCB. Structural indices of subchondral trabecular bone (STB) were significantly lower in OP than in OA samples. Conclusion: Thinning of SCB, found in OP samples with higher Mankin scores could be related with the progression of the cartilage degeneration indicating an early-stage OA. Increased levels of bone remodeling and evidently changed morphology of subchondral bone found in OP samples with lower Mankin score indicated that bony bed level must have a role in the progression of the cartilage degeneration. [Copyright &y& Elsevier]

Summary: Objective: Bisphosphonates are considered potential disease modifying osteoarthritis (OA) agents. The present study investigated the efficacy of pre-emptive, early, and delayed alendronate (ALN) treatment initiation on subchondral trabecular bone and cartilage in low-dose monosodium iodoacetate (MIA)-induced knee OA in rats. Methods: Male rats received pre-emptive (n = 12, day 0–end of week 2), early (n = 12, end of week 2–end of week 6), or delayed (n = 12, end of week 6–end of week 10) ALN treatment (30 μg/kg/week). Pre-emptive ALN-treated rats were scanned using in vivo micro-computed tomography (micro-CT) after 2 weeks and then sacrificed, early ALN-treated rats were scanned after 2 and 6 weeks and sacrificed, and the delayed ALN-treated rats were scanned after 2, 6, and 10 weeks of OA induction and sacrificed. After sacrifice, bone histomorphometry and histology of the tibia and biomarker analyses were undertaken. Changes in hind limb weight-bearing were assessed from day −1 until day 14. Results: MIA-induced pathological features similar to progressive human OA in the cartilage and subchondral bone. Pre-emptive ALN treatment preserved subchondral trabecular bone microarchitecture, prevented bone loss, decreased bone turnover and joint discomfort. Pre-emptive ALN treatment had moderate effects on cartilage degradation. Early and delayed ALN treatments prevented loss of trabeculae and decreased bone turnover, but had no significant effect on cartilage degradation. Conclusion: ALN prevented increased bone turnover and preserved the structural integrity of subchondral bone in experimental OA. The time point of treatment initiation is crucial for treating OA. Treating both the subchondral bone and cartilage in OA would be clinically more beneficial. [Copyright &y& Elsevier]

Previous reports indicate a potential role for calcitonin (CT) in the treatment of osteoarthritis (OA). To evaluate this potential therapeutic role, we investigated the effect of CT pretreatment on the activation of mitogen-activated protein kinase (MAPK) signaling and the expression of matrix metalloproteinase-13 (MMP-13) in interleukin-1β (IL-1β)-induced chondrocytes, and further assessed its protective effect in a rat model of anterior cruciate ligament transection (ACLT), using sham-operated and saline-treated controls. Using western blotting in vitro, we found that CT pretreatment inhibited the IL-1β-induced phosphorylation of 38,000-dalton protein (p38) and extracellular regulated protein 1/2 (ERK1/2) and reduced the expression of MMP-13 protein. For the in vivo experiment, 30 male rats were randomly divided into three groups of 10, subjected to bilateral ACLT or sham surgery, and then treated for 12 weeks with subcutaneous injections of CT or normal saline. Histological observations showed that CT treatment reduced the severity of the cartilage lesions stemming from the ACLT surgery and provided a lower Mankin score when compared with that determined for rats in the saline-treated ACLT group. Immunohistochemical staining revealed that CT treatment increased type II collagen expression and decreased MMP-3 and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) expression when compared with the saline-treated group. Subchondral bone analysis indicated that CT treatment inhibited the reduction in bone mineral density observed in the saline-treated ACLT group and reduced the ACLT-induced destruction to the subchondral trabecular microstructure. Our data demonstrate that CT induces its protective effects by reducing the chondrocyte response to inflammatory stimuli, cartilage extracellular matrix degradation, and subchondral trabecular microstructure damages brought on by OA. [ABSTRACT FROM AUTHOR]

Summary: Objective: With developments in clinical computed tomography (CT), in vivo analysis of patients’ bone microstructure has become increasingly possible. We analyzed the subchondral trabecular bone of hip osteoarthritis (OA) patients using multi-detector row CT (MDCT) to closely examine the structural changes that occur as OA progresses. Design: 47 female hip joints were studied: 20 with OA secondary to hip dysplasia (11 advanced OA, nine early-moderate OA), seven with hip dysplasia without OA, and 20 normal. The images’ maximal spatial resolution was 280×280×500μm. Regions of interest (ROIs) were the subchondral trabecular bones of the acetabulum and femoral head. Measurement parameters were bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), structure model index (SMI), trabecular bone pattern factor (TBPf), Euler’s number, and degree of anisotropy (DA). Relationships between joint space volume and these parameters were analyzed. Results: With decreasing joint space, Tb.Th and BV/TV increased, and Tb.Sp, Tb.N, SMI, TBPf, and DA decreased significantly. The microstructures were significantly different between the early to advanced OA groups and the normal and dysplasia groups; there was no significant difference between the normal and dysplasia groups. Conclusions: Changes of subchondral trabecular bone structure in OA could be evaluated using MDCT, despite imperfect spatial resolution and limited accuracy. Trabecular bone thickening and associated structural changes may be closely related to OA. Changes were observed in early to advanced OA, but not in dysplasia. This method may help to further elucidate OA pathogenesis, determine the therapeutic strategy, and evaluate therapy. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is no longer regarded as a simple wear-and-tear problem of articular cartilage. Instead, OA is a whole joint disorder involving both cartilaginous and non-cartilaginous tissues such as subchondral bone and synovium. Among them, subchondral bone undergoes constant remodeling in response to the changes of mechanical environment. Current understanding of subchondral bone disturbance in OA is limited to its link with an altered local mechanical loading as a result of ligament or meniscus injury. Very recently, hypertension, the most common vascular morbidity, has been emerged as an independent risk factor of OA. It might suggest a plausible role of systemic hemodynamic mechanical stress in subchondral bone remodeling and the pathogenesis of OA. However, their relationship remains not fully understood. Based on our preliminary clinical observation on the association of hemodynamic parameters with subchondral bone mass and microstructure in late-stage knee OA patients, we formulate a vascular etiology hypothesis of OA from a mechanobiology perspective. Noteworthily, hemodynamic stress associated with subchondral bone mineral density; yet compressive mechanical loading does not. Furthermore, hemodynamic parameters positively correlated with subchondral plate-like trabecular bone volume but negatively associated with rod-like trabecular bone volume. In contrast, compressive mechanical loading tends to increase both plate-like and rod-like trabecular bone volume. Taken together, it warrants further investigations into the distinct role of hemodynamic or compressive stress in shaping subchondral bone in the pathophysiology of OA., The Translational Potential of This Article: This work provides a new insight, from the angle of biomechanics, into the emerging role of vascular pathologies, such as hypertension, in the pathogenesis of OA. It might open up a new avenue for the development of a mechanism-based discovery of novel diagnostics and therapeutics., (© 2021 The Authors.)

According to the Chinese medicine, magnoflorine exerted significant anti-inflammatory effects and potentially promoted synthesis of proteoglycans in chondrocytes to reverse the progression of rheumatoid arthritis. However, the latent beneficial effect of magnoflorine for the treatment of traumatic osteoarthritis (OA) is still unknown. Therefore, we aim to demonstrate the efficacy of magnoflorine combined with HA-gel in attenuating cartilage degeneration in anterior cruciate ligament transection (ACLT) induced OA rat model. We found that the histological results showed the elevated cartilage matrix, chondrogenic signals and chondroprogenitor cells in HA-gel + magnoflorine treatment. HA-gel + magnoflorine treatment resulted in a decreased modified Mankin's score, and a higher volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and HC/Sum (whole cartilage), compared to ACLT and HA-gel groups. Furthermore, both the volume ratios of HC/Sum and HC/CC were negatively correlated with modified Mankin's scores. Finally, HA-gel + magnoflorine could significantly increase the BV/TV, Tb.Th, and decrease the Tb.Pf, Po(tot), Conn.Dn and Tb.Sp. In vitro , 50 μg/ml magnoflorine treatment could significantly increase the viability, S-phase, migration rate and chondrogenesis of chondroprogenitor cells. There were significant downregulations of MAPK/NF-κB signaling, and upregulations of chondrogenic signals in 50 μg/ml magnoflorine treatment. There were significant downregulations of proinflammatory cytokines and upregulation of IL-10 in HA-gel + magnoflorine treated group. Therefore, our study elucidated a protective effect of HA-gel + magnoflorine on attenuating cartilage degradation and maintaining SCB stabilization in ACLT induced OA. [ABSTRACT FROM AUTHOR]

Objective: To investigate the mitigate efficacy of Chinese medicine Lingzhi (LZ) and San-Miao-San (SMS) combined with hyaluronic acid (HA)-gel in attenuating cartilage degeneration in traumatic osteoarthritis (OA)., Methods: The standardized surgery of anterior cruciate ligament transection (ACLT) was made from the medial compartment of right hind limbs of 8-week-old female SD rats and resulted in a traumatic OA. Rats (n ​= ​5/group) were treated once intra-articular injection of 50 ​μl HA-gel, 50 ​μl HA-gel+50 ​μg LZ-SMS, 50 ​μl of saline+50 ​μg LZ-SMS and null (ACLT group) respectively, except sham group. Limbs were harvested for μCT scan and histopathological staining 3-month post-treatment. Inflammatory cytokines from plasma and synovial fluid were detected using Immunology Multiplex Assay kit. The putative targets of active compounds in LZ-SMS and known therapeutic targets for OA were combined to construct protein-protein interaction network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was adopted to predict the potential targets and signaling pathway of LZ-SMS in OA through the tool of DAVID Bioinformatics., Results: In vivo , HA-gel ​+ ​LZ-SMS treatment resulted in a higher volume ratio of hyaline cartilage (HC)/calcified cartilage (CC) and HC/Sum (total volume of cartilage), compared to ACLT and HA-gel groups. In addition, histological results showed the elevated cartilage matrix, chondrogenic and osteoblastic signals in HA-gel ​+ ​LZ-SMS treatment. Treatment also significantly altered subchondral bone (SCB) structure including an increase in BV/TV, Tb.Th, BMD, Conn.Dn, Tb.N, and DA, as well as a significant decrease in Tb.Sp and Po(tot), which implied a protective effect on maintaining the stabilization of tibial SCB microstructure. Furthermore, there was also a down-regulated inflammatory cytokines and upregulated anti-inflammatory cytokine IL-10 in HA+LZ-SMS group. Finally, 64 shared targets from 37 active compounds in LZ-SMS related to the core genes for the development of OA. LZ-SMS has a putative role in regulating inflammatory circumstance through influencing the MAPK signaling pathway., Conclusion: Our study elucidated a protective effect of HA-gel ​+ ​LZ-SMS in mitigating cartilage degradation and putative interaction with targets and signaling pathway for the development of traumatic OA., The Translational Potential of This Article: Our results provide a biological rationale for the use of LZ-SMS as a potential candidate for OA treatment., Competing Interests: The authors have no conflicts of interest to disclose in relation to this article., (© 2020 The Author(s).)

Introduction: Bone marrow lesions (BMLs) are frequently identified by MRI in the subchondral bone in knee osteoarthritis (KOA). BMLs are known to be closely associated with joint pain, loss of the cartilage and structural changes in the subchondral trabecular bone (SCTB). Despite this, understanding of the nature of BMLs at the trabecular tissue level is incomplete. Thus, we used Raman microspectroscopy to examine the biochemical properties of SCTB from KOA patients with presence or absence of BMLs (OA-BML, OA No-BML; respectively), in comparison with age-matched cadaveric non-symptomatic controls (Non-OA CTL)., Methods: Tibial plateau (TP) specimens were collected from 19 KOA arthroplasty patients (6-Male, 13-Female; aged 56-74 years). BMLs were identified ex-vivo by MRI, using PDFS- and T1-weighted sequences. The KOA specimens were then categorized into an OA-BML group (n = 12; containing a BML within the medial condyle only) and an OA No-BML group (n = 7; with no BMLs identified in the TP). The control (CTL) group consisted of Non-OA cadaveric TP samples with no BMLs and no macroscopic or microscopic evidence of OA-related changes (n = 8; 5-Male, 3-Female; aged 44-80 years). Confocal Raman microspectroscopy, with high spatial resolution, was used to quantify the biochemical properties of SCTB tissue of both the medial and the lateral condyle in each group., Results: The ratios of peak intensity and integrated area of bone matrix mineral (Phosphate (v1), Phosphate (v2) and Phosphate (v4)), to surrogates of the organic phase of bone matrix (Amide I, Proline and Amide III), were calculated. Within the medial compartment, the mineral:organic matrix ratios were significantly lower for OA-BML, compared to Non-OA CTL. These ratios were also significantly lower for the OA-BML medial compartment, compared to the OA-BML lateral compartment. There were no group or compartmental differences for Carbonate:Phosphate (v1, v2 and v4), Amide III (α-helix):Amide III (random-coil), Hydroxyproline:Proline, or Crystallinity., Conclusion: As measured by Raman microspectroscopy, SCTB tissue in BML zones in KOA is significantly less mineralized than the corresponding zones in individuals without OA. These data are consistent with those obtained using other methods (e.g. Fourier transform infrared spectroscopy; FTIR) and with the increased rate of bone remodeling observed in BML zones. Reduced mineralization may change the biomechanical properties of the trabecular bone in BMLs and the mechanical interaction between subchondral bone and its overlying cartilage, with potential implications for the development and progression of OA., Competing Interests: All authors declare that they have no conflict of interest regarding the work., (© 2020 The Authors.)

Objective: Developmental dysplasia of the hip (DDH) is recognized as a frequent cause of secondary osteoarthritis (OA). The purpose in this study was to compare structural and biomechanical properties of subchondral trabecular bone ​and its relationship with cartilage damage between patients with DDH and patients with primary hip OA., Methods: Forty-three femoral head specimens obtained from patients who underwent total hip arthroplasty [DDH, n ​= ​17; primary OA, n ​= ​16; and normal control (NC), n ​= ​10] were scanned by microcomputed tomography and analyzed by individual trabecula segmentation to obtain the microstructural types of subchondral trabecular bone. The biomechanical properties were analyzed by micro-finite element analysis, and cartilage damage was evaluated by histology. The linear regression analysis was used to indicate the association between microstructures, biomechanical property, and articular cartilage., Results: The DDH group showed the lowest total bone volume fractions (BV/TV) and plate BV/TV in the three groups (p ​< ​0.05). There were also different discrepancies between the three groups in plate/rod trabecular number, plate/rod trabecular thickness, trabecular plate surface area/trabecular rod length, and junction density with different modes (plate-plate, rod-rod, and plate-rod junction density). The micro-finite element analysis, histology, and linear regression revealed that the subchondral trabecular bone in the DDH group had inferior biomechanical properties ​and cartilage damage of patients with DDH was more serious with different subchondral trabecular bone microstructures., Conclusion: Our findings detected deteriorating subchondral trabecular bone microstructures in patients with DDH. The mass and type of subchondral trabecular bone play a key role in mechanical properties in DDH, which might be related to cartilage damage., The Translational Potential of This Article: Our findings suggested that changes of subchondral trabecular bone play a critical role ​in DDH progression and that the improvement on subchondral trabecular bone may be a sensitive and promising way in treatment of DDH., (© 2019 The Authors.)

Developing effective treatment for osteoarthritis (OA), a prevalent and disabling disease, has remained a challenge, primarily because of limited understanding of its pathogenesis and late diagnosis. In the subchondral bone, rapid bone loss after traumatic injuries and bone sclerosis at the advanced stage of OA are well-recognized hallmarks of the disease. Recent studies have further demonstrated the crucial contribution of subchondral bone in the development of OA. However, the microstructural basis of these bone changes has not been examined thoroughly, and the paradox of how abnormal resorption can eventually lead to bone sclerosis remains unanswered. By applying a novel microstructural analysis technique, individual trabecula segmentation (ITS), to micro-computed tomography (μCT) images of human OA knees, we have identified a drastic loss of rod-like trabeculae and thickening of plate-like trabeculae that persisted in all regions of the tibial plateau, underneath both severely damaged and still intact cartilage. The simultaneous reduction in trabecular rods and thickening of trabecular plates provide important insights to the dynamic and paradoxical subchondral bone changes observed in OA. Furthermore, using an established guinea pig model of spontaneous OA, we discovered similar trabecular rod loss and plate thickening that preceded cartilage degradation. Thus, our study suggests that rod-and-plate microstructural changes in the subchondral trabecular bone may play an important role in the development of OA and that advanced microstructural analysis techniques such as ITS are necessary in detecting these early but subtle changes. With emerging high-resolution skeletal imaging modalities such as the high-resolution peripheral quantitative computed tomography (HR-pQCT), trabecular rod loss identified by ITS could potentially be used as a marker in assessing the progression of OA in future longitudinal studies or clinical diagnosis. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)