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Methylprednisolone (MPS) use is linked to increased cases of osteonecrosis of the femoral head (ONFH). Bone marrow mesenchymal stem cells (BMSCs) have shown potential for treating MPS-induced ONFH, but their effectiveness is limited by high apoptosis rates post-transplantation. We developed a pretreatment strategy for BMSCs to improve their viability. In a rat model of MPS-induced ONFH, we evaluated the effects of USP13 overexpression in BMSCs through micro-CT, HE staining, and TUNEL staining. USP13-overexpressing BMSCs significantly reduced ONFH severity compared to plain BMSCs and direct lentivirus injection. USP13 also protected BMSCs from MPS-induced apoptosis by modulating PTEN and reducing AKT phosphorylation. This led to decreased expression of apoptotic genes and proteins in USP13-overexpressing BMSCs. Our findings highlight USP13 as a promising target for enhancing BMSC survival and efficacy in treating MPS-induced ONFH., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Rotatory devices are essential in clinical surgical practice, however, depending on the different systems available, their function can impact bone repair and postoperative responses on varying scales. This impact underscores the need to explore new techniques aiming to enhance bone repair. This study aimed to assess the immediate and delayed effects on bone healing in subcritical bone defects using both air turbine and an electric handpiece. For this purpose, 40 male Wistar rats were allocated into two groups. The Control Group (CG) had bone defect made using an air turbine device, while the Experimental Group (EG) had defects made using an electric handpiece. Ten animals were sacrificed for each time of evaluation. Bone neoformation, microstructure, and collagen organization were assessed ate 7, 15 and 30 days postoperative. Inflammatory profiling was conducted at 7 and 15 days. Immediate thermal osteonecrosis were evaluated after the use of rotary systems. Multivariate analysis was used to access statistical differences. The EG exhibited enhanced parameters of bone neoformation in all analyses, with statistical difference between 15 and 30 days (P = .0002) and in comparison with CG in 30 days (P = .0009). A reduced number of inflammatory cells and increased angiogenesis in the initial periods was seen in EG, corroborating the consistent values of collagen type 1 and a decrease of collagen type 3 over times. Immediate thermal osteonecrosis was statistically higher for the CG (P < .05), which showed adequate neoformation of subcritical defects but consistently lower values than those found in the EG. These data suggest that the electric handpiece demonstrated more bone repair area, proving to be an excellent alternative to surgical practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sol et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bone metastasis and steroids are known to activate the coagulation system and induce osteoporosis, pathological bone fractures, and bone pain. Heparanase is a protein known to enhance the hemostatic system and to promote angiogenesis, metastasis, and inflammation. The objective of the present study was to evaluate the effects of steroids and malignancy on the coagulation factors and osteoblast activity in the bone tissue. The effects of dexacort and malignant medium were evaluated in osteoblasts derived from human bone marrow mesenchymal stem cells and human umbilical vein endothelial cells (HUVECs). The bones of mice treated with dexacort for 1 month were studied. Bone biopsies of ten patients with bone metastasis, ten with steroid-induced avascular necrosis (AVN), and ten with osteoarthritis were compared to ten controls. We found that dexacort and malignant medium significantly increased the heparanase levels in osteoblasts and HUVECs and decreased the levels of alkaline phosphatase (ALKP). Peptide 16AC, derived from heparanase, which interacts with tissue factor (TF), further increased the effect, while peptide 6, which inhibits interactions between heparanase and TF, reversed the effect in these cells. The bone microcirculation of mice treated with dexacort exhibited significantly higher levels of heparanase, TF, TF pathway inhibitor (TFPI), TFPI-2, thrombin, and syndecan-1, but reduced levels of osteocalcin and ALKP. The pathological human bone biopsies' microcirculation exhibited significantly dilated blood vessels and higher levels of heparanase, TF, TFPI, TFPI-2, and fibrin. In summary, steroids and malignancy increased the activation of the coagulation system in the bone microcirculation and reduced the osteoblast activity. Heparanase inhibitors should be further investigated to attenuate bone fractures and pain.

Glucocorticoids (GCs) are key inducers of osteonecrosis, yet not all patients treated with GCs develop glucocorticoid-associated osteonecrosis (GAON). The factors mediating this relationship are unclear. Studies have shown that gut microbiota and their metabolites influence bone metabolism, but their role in GAON is unclear. This study aimed to explore the connection between GAON and gut microbiota. Through bidirectional Mendelian randomization analysis, we identified 14 gut microbial taxa, including Lachnospiraceae (IVW, P = 0.011), associated with GAON. RNA-seq analysis revealed that GAON differentially expressed genes (DEGs) were enriched for intestinal inflammatory response mechanisms. We then compared patients who developed GAON (17 cases), those who did not (GAnON, 15 cases), and those untreated with GCs (Blank, 15 cases) for gut microbiota composition, short-chain fatty acids (SCFAs), and serum inflammatory factors. Our findings indicated a decrease in Lachnospiraceae abundance (GAON 17.13%, GAnON 12.51%, Blank 24.52%) in GC-treated patients. Serum inflammatory factors (IL-17 A, IL-33, and TNF-α) associated with GAON (59.603 ± 12.147, 89.337 ± 20.714, 42.584 ± 9.185) showed significant differences between Blank (1.446 ± 0.683, 11.534 ± 4.705, 4.682 ± 1.48) and GAnON (25.353 ± 8.181, 32.527 ± 7.352, 12.49 ± 3.217) groups, with a negative correlation between these factors and Lachnospiraceae levels. Butyric acid levels in SCFAs varied among groups (P<0.01) and correlated with Lachnospiraceae and inflammatory factors. Controlled experiments in GAON rats demonstrated butyric acid's osteoprotective role in GAON development (P<0.01). In conclusion, our study suggests that reduced Lachnospiraceae and butyric acid levels, along with increased inflammation due to GCs use, contribute to GAON. Butyric acid may mediate the effects of Lachnospiraceae and inflammation. Butyrate supplementation could potentially reduce GAON incidence, offering a novel approach for its clinical management., Competing Interests: Declarations Ethics approval and consent to participate Sample collection was approved by the Ethics Committee at Jiangsu Provincial Hospital of Traditional Chinese Medicine (No. 2023NL-037-01). All volunteers voluntarily donated their own discarded femoral head specimens, stools, blood and signed an informed consent form. All animal experiments were approved by the Animal Ethics Committee of Nanjing University of Chinese Medicine (202306A059), and were conducted according to the National Research Council Guide for Care and Use of Laboratory Animals. Competing interests No potential conflict of interest was reported by the author(s)., (© 2024. The Author(s).)

Ischemic osteonecrosis, particularly glucocorticoid-induced osteonecrosis of the femoral head (GIONFH), is primarily due to the dysfunction of osteogenesis and angiogenesis. miRNA, as a therapeutic system with immense potential, plays a vital role in the treatment of various diseases. However, due to the unique microenvironmental structure of bone tissue, especially in the case of GIONFH, where there is a deficiency in the vascular system, it is challenging to effectively target and deliver to the ischemic osteonecrosis area. A drug delivery system assisted by genetically engineered cell membranes holds promise in addressing the challenge of targeted miRNA delivery. Herein, we leverage the potential of miR-21 in modulating osteogenesis and angiogenesis to design an innovative biomimetic nanoplatform system. First, we employed metal-organic frameworks (MOFs) as the core structure to load miR-21-m (miR-21-m@MOF). The nanoparticles were further coated with the membrane of bone marrow mesenchymal stem cells overexpressing CXCR4 (CM-miR-21-m@MOF), enhancing their ability to target ischemic bone areas via the CXCR4-SDF1 axis. These biomimetic nanocomposites possess both bone-targeting and ischemia-guiding capabilities, actively targeting GIONFH lesions to release miR-21-m into target cells, thereby silencing PTEN gene and activating the PI3K-AKT signaling pathway to regulate osteogenesis and angiogenesis. This innovative miRNA delivery system provides a promising therapeutic avenue for GIONFH and potentially other related ischemic bone diseases. STATEMENT OF SIGNIFICANCE., Competing Interests: Declaration competing of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objective: To report a common site of external ear canal erosion in multiple pathologies, located inferiorly at 6 o'clock., Patients: Otology patients who came in 2023 for treatment of external auditory canal erosions., Intervention: This clinical capsule is an observational report of the external canal's propensity to erosion at the 6 o'clock location. Patient treatments were canalplasty, mastoidectomy, and medical management., Main Outcome Measure: Documentation of the propensity to erosion at the 6 o'clock location in the external auditory canal. Locations of the niduses of prior series of external auditory canal pathologies are documented., Results: Eight patients are presented with external auditory canal erosion in 10 ears originating at the 6 o'clock position medial to the bony-cartilaginous junction. No other patient with spontaneous canal erosion presented with their nidus of pathology in another canal location. (A review of 42 case series of 291 patients found that keratosis obturans and bisphosphonate-induced osteonecrosis tended to arise from the same 6 o'clock lateral bony canal location, while 26% of necrotizing otitis externa cases arose there.)., Conclusions: The "6 o'clock spot" in the external canal is a common location of canal erosion for spontaneous wax and keratin collections and may be the precursor to keratosis obturans, bisphosphonate-induced osteonecrosis of the ear canal, and necrotizing otitis externa., Competing Interests: The authors have no conflicts of interest to report, and this study had no funding., (Copyright © 2024, Otology & Neurotology, Inc.)

Osteonecrosis (ON) of the femoral head (ONFH) is a devastating bone disease affecting over 20 million people worldwide. ONFH is caused by a disruption of the blood supply, leading to necrotic cell death and increased inflammation. Macrophages are the key cells mediating the inflammatory responses in ON. It is unclear what the dynamic phenotypes of macrophages are and what mechanisms may affect macrophage polarization and, therefore, the healing process. In our preliminary study, we found that there is an invasion of macrophages into the repair tissue during ON healing. Interestingly, in both ONFH patients and a mouse ON model, fat was co-labeled within macrophages using immunofluorescence staining, indicating the phagocytosis of fat by macrophages. To study the effects of fat phagocytosis on the macrophage phenotype, we set up an in vitro macrophage and fat co-culture system. We found that fat phagocytosis significantly decreased M1 marker expression, such as IL1β and iNOS, in macrophages, whereas the expression of the M2 marker Arg1 was significantly increased with fat phagocytosis. To investigate whether the polarization change is indeed mediated by phagocytosis, we treated the cells with Latrunculin A (LA, which inhibits actin polymerization and phagocytosis). LA supplementation significantly reversed the polarization marker gene changes induced by fat phagocytosis. To provide an unbiased transcriptional gene analysis, we submitted the RNA for bulk RNA sequencing. Differential gene expression (DGE) analysis revealed that the top upregulated genes were related to anti-inflammatory responses, while proinflammatory genes were significantly downregulated. Additionally, using pathway enrichment and network analyses (Metascape), we confirmed that gene-enriched categories related to proinflammatory responses were significantly downregulated in macrophages with fat phagocytosis. Finally, we validated the similar macrophage phenotype changes in vivo. To summarize, we discovered that fat phagocytosis occurs in both ONFH patients and an ON mouse model, which inhibits proinflammatory responses with increased anabolic gene expression in macrophages. This fat-phagocytosis-induced macrophage phenotype is consistent with the in vivo changes shown in the ON mouse model. Our study reveals a novel phagocytosis-mediated macrophage polarization mechanism in ON, which fills in our knowledge gaps of macrophage functions and provides new concepts in macrophage immunomodulation as a promising treatment for ON.

Background: Osteonecrosis of the femoral head caused by glucocorticoids (GIONFH) is a significant issue resulting from prolonged or excessive clinical glucocorticoid use. Astaxanthin, an orange-red carotenoid present in marine organisms, has been the focus of this study to explore its impact and mechanism on osteoblast apoptosis induced by dexamethasone (Dex) and GIONFH., Methods: In this experiment, bioinformatic prediction, molecular docking and dynamics simulation, cytotoxicity assay, osteogenic differentiation, qRT-PCR analysis, terminal uridine nickend labeling (TUNEL) assay, determination of intracellular ROS, mitochondrial function assay, immunofluorescence, GIONFH rat model construction, micro-computed tomography (micro-CT) scans were performed., Results: Our research demonstrated that a low dose of astaxanthin was non-toxic to healthy osteoblasts and restored the osteogenic function of Dex-treated osteoblasts by reducing oxidative stress, mitochondrial dysfunction, and apoptosis. Furthermore, astaxanthin rescued the dysfunction in poor bone quality, bone metabolism and angiogenesis of GIONFH rats. The mechanism behind this involves astaxanthin counteracting Dex-induced osteogenic damage by activating the Nrf2 pathway., Conclusion: Astaxanthin shields osteoblasts from glucocorticoid-induced oxidative stress and mitochondrial dysfunction via Nrf2 pathway activation, making it a potential therapeutic agent for GIONFH treatment., (© 2024. The Author(s).)

Autophagy may play an important role in the occurrence and development of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC-ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC-ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC-induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC-ONFH was used for evaluating the therapeutic effect of oral lithium on GC-ONFH and underlying mechanism. Findings demonstrated that GC over-activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over-activated autophagy of GC-treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC-ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over-activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up-regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC-ONFH. Lithium may be a promising therapeutic agent for GC-ONFH. However, the role of autophagy in the pathogenesis of GC-ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC-ONFH, and the efficacy of lithium in the treatment of GC-ONFH and its underlying mechanisms., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Failure of endochondral ossification due to interruption of the vascular supply to the epiphyseal cartilage is a critical step in the development of osteochondritis dissecans (OCD). Herein we describe the vascular architecture of the distal humeral epiphyseal cartilage in pigs and identify characteristic features that have been associated with sites predisposed to OCD development across species. Distal humeral specimens were harvested from pigs (n = 5, ages = 1, 10, 18, 30, and, 42 days old) and imaged at 9.4T magnetic resonance imaging (MRI) using a 3D gradient recalled echo sequence. The MRI data were processed using a quantitative susceptibility mapping (QSM) pipeline to visualize the vascular architecture. Specimens were also evaluated histologically to identify the presence of ischemic epiphyseal cartilage necrosis (osteochondrosis [OC]-latens) and associated failure of endochondral ossification (OC-manifesta). The QSM data enabled visualization of two distinct vascular beds arising from the perichondrium at the lateral and medial aspects of the distal humeral epiphysis. Elongated vessels originating from these beds coursed axially to supply the lateral and medial thirds of epiphyseal cartilage. At 18 days of age and older, a shift from perichondrial to transosseous blood supply was noted axially, which appeared more pronounced on the lateral side. This shift coincided with histologic identification of OC-latens (30- and 42-day-old specimens) and OC-manifesta (18- and 42-day-old specimens) lesions in the corresponding regions. The vascular anatomy and its evolution at the distal humeral epiphysis closely resembles that previously reported at predilection sites of knee OCD, suggesting a shared pathophysiology between the knee and elbow joints., (© 2023 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

This article defines the fascial and spatial anatomy of the suprahyoid neck region, delineates the role of CT and MR imaging, discusses the inflammatory conditions of the jaws and adjacent spaces and their clinical symptomatology, and illustrates the appearance of these conditions., Competing Interests: Disclosure The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this comprehensive case report, we examine a 29-year-old male who suffered a high-energy vehicular accident, resulting in a type III Hawkins fracture of the talus. This specific fracture type is critically associated with a greater than 90% risk of progressing to avascular necrosis (AVN) of the talus, a severe and debilitating condition. Alongside this, the patient sustained fractures of the medial and lateral malleolus. Due to extensive swelling and severe circulatory disorders, an immediate emergency surgical procedure was necessitated, employing nail fixation as a stabilizing intervention. Over the course of 12 months following the surgery, despite routine post-operative imaging including X-rays and computed tomography (CT) scans, the patient continued to experience significant pain and impairment. This condition led to further investigations, culminating in a magnetic resonance imaging (MRI) that revealed an area of 19.8∕20.9 mm of AVN on the talus dome's upper-lateral facet. Interestingly, earlier CT scans had indicated multiple osteitic lesions, but these findings lacked a clear clinical correspondence, presenting a diagnostic challenge. To resolve this ambiguity and to definitively distinguish between necrosis and infection, a targeted histopathological analysis was deemed necessary. This analysis was conducted on a bone fragment extracted during a follow-up surgical procedure for nail removal. The results from this analysis present an area of bone and myeloid tissue necrosis unequivocally confirming the presence of AVN, effectively ruling out osteitis as a potential diagnosis. This critical diagnostic clarification allowed for a shift in therapeutic strategy, enabling the initiation of a more focused and potentially curative treatment regimen.

Osteonecrosis of the femoral head (ONFH) is a devastating bone disease that is caused by a disruption of blood supply leading to necrotic cell death. Clinically, it was found that obesity has a high prevalence with ONFH. However, it remains unclear how obesity may directly affect tissue regeneration and bone healing in osteonecrosis (ON). The purpose of this study is to investigate the effects of obesity and weight loss (WL) on ON healing. In this study, we induced obesity and WL in an established surgery-induced ON mouse model via feeding a high-fat diet (HFD) and altering the diet respectively. All mice received a surgical induction of ON of distal femoral epiphysis at the age of 12 weeks. HFD was switched to normal diet (ND) after ON surgery to induce WL. Mouse body weight was recorded weekly. Mouse body composition was scanned by DEXA (Dual-energy X-ray absorptiometry) right after sacrifice at the age of 16 weeks. The distal femoral bone samples were fixed and embedded for histology such as H&E, immunohistochemistry, and TRAP staining. In this study, we found that HFD-induced obesity impaired revascularization and bone remodeling showing decreased vessel areas and reduced osteoblast and osteoclast numbers. WL could rescue obesity-induced bone healing defects. Our study is the first to test the direct effects of obesity and WL on ON bone healing. We believe our work may provide new concepts for osteonecrosis treatment in obese patients., (© 2023 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Oxidative stress plays a crucial role in steroid-induced osteonecrosis of the femoral head (SONFH). Although several antioxidant strategies have been investigated for treating SONFH, their antioxidant efficiencies and therapeutic effects remain unsatisfactory. Here, we developed a selenium nanoparticles/carboxymethyl chitosan/alginate (SeNPs/CMC/Alg) antioxidant hydrogel and evaluated its ability to treat SONFH. In vitro assays indicated that the SeNPs/CMC/Alg hydrogel exhibited excellent properties, such as low cytotoxicity, sustained SeNPs release, and favorable antioxidant activity. Under oxidative stress, the SeNPs/CMC/Alg hydrogel promoted reactive oxygen species (ROS) elimination and enhanced the osteogenic and proangiogenic abilities of bone marrow mesenchymal stem cells (BMSCs). After establishing a rabbit model of SONFH, the SeNPs/CMC/Alg hydrogel was transplanted into the femoral head after core decompression (CD) surgery. Radiographic and histological analyses revealed that the hydrogel treatment alleviated SONFH by eliminating ROS and promoting osteogenesis and angiogenesis compared to those in the CD and CMC/Alg groups. In vitro and in vivo studies indicated that the Wnt/β-catenin signaling pathway was activated by the SeNPs/CMC/Alg hydrogel in both hydrogen peroxide-conditioned BMSCs and necrotic femoral heads. These findings indicate that local transplantation of the SeNPs/CMC/Alg hydrogel is beneficial for treating SONFH, as it promotes ROS elimination and activation of the Wnt/β-catenin signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glucocorticoid-induced osteonecrosis of the femoral head (GONFH) is a common refractory joint disease characterized by bone damage and the collapse of femoral head structure. However, the exact pathological mechanisms of GONFH remain unknown. Here, we observed abnormal osteogenesis and adipogenesis associated with decreased β-catenin in the necrotic femoral head of GONFH patients. In vivo and in vitro studies further revealed that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation of bone marrow mesenchymal cells (BMSCs) by inhibiting β-catenin signaling in glucocorticoid-induced GONFH rats. Col2 + lineage largely contributes to BMSCs and was found an osteogenic commitment in the femoral head through 9 mo of lineage trace. Specific deletion of β-catenin gene ( Ctnnb1 ) in Col2 + cells shifted their commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice. Overall, we uncover that β-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of GONFH and identify an ideal genetic-modified mouse model of GONFH., Competing Interests: CX, HX, LF, JC, WY, DF, XW, BH, LX, CW, PT, DC, PW, HJ No competing interests declared, (© 2023, Xia, Xu et al.)

Perfusion imaging is the aspect of functional imaging, which is most applicable to the musculoskeletal system. In this review, the anatomy and physiology of bone perfusion is briefly outlined as are the methods of acquiring perfusion data on MR imaging. The current clinical indications of perfusion related to the assessment of soft tissue and bone tumors, synovitis, osteoarthritis, avascular necrosis, Keinbock's disease, diabetic foot, osteochondritis dissecans, and Paget's disease of bone are reviewed. Challenges and opportunities related to perfusion imaging of the musculoskeletal system are also briefly addressed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Core decompression (CD) with mesenchymal stromal cells (MSCs) is an effective therapy for early-stage osteonecrosis of the femoral head (ONFH). Preconditioning of MSCs, using inflammatory mediators, is widely used in immunology and various cell therapies. We developed a three-dimensional printed functionally graded scaffold (FGS), made of β-TCP and PCL, for cell delivery at a specific location. The present study examined the efficacy of CD treatments with genetically modified (GM) MSCs over-expressing PDGF-BB (PDGF-MSCs) or GM MSCs co-over-expressing IL-4 and PDGF-BB and preconditioned for three days of exposure to lipopolysaccharide and tumor necrosis factor-alpha (IL-4-PDGF-pMSCs) using the FGS for treating steroid-induced ONFH in rabbits. We compared CD without cell-therapy, with IL-4-PDGF-pMSCs alone, and with FGS loaded with PDGF-MSCs or IL-4-PDGF-pMSCs. For the area inside the CD, the bone volume in the CD alone was higher than in both FGS groups. The IL-4-PDGF-pMSCs alone and FGS + PDGF-MSCs reduced the occurrence of empty lacunae and improved osteoclastogenesis. There was no significant difference in angiogenesis among the four groups. The combined effect of GM MSCs or pMSCs and the FGS was not superior to the effect of each alone. To establish an important adjunctive therapy for CD for early ONFH in the future, it is necessary and essential to develop an FGS that delivers biologics appropriately and provides structural and mechanical support., (© 2023 Wiley Periodicals LLC.)

Purpose: The purpose of this study was to assess CBCT scans of patients with medication related osteonecrosis of the jaws (MRONJ), osteoradionecrosis (ORN), osteomyelitis (OM) and jaw metastatic disease (JM), evaluate the presence and extent of radiologic findings, identify radiologic parameters that may distinguish the four entities and last, introduce a new modified radiographic index (CRIm), in order to contribute to the diagnosis of these conditions., Methods: Τwo major databases were retrospectively searched for fully documented and diagnosed CBCT scans of MRONJ, ORN, OM and JM from 2006 to 2019. 335 CBCT scans met the inclusion criteria and were assessed under standardized viewing conditions blindly by 2 observers. The CRIm index proposed in this study evaluates: lytic changes, sclerosis, periosteal bone formation, sequestration, non-healing extraction sockets and other findings which included: sinus implication, inferior alveolar canal implication and jaw fracture. Lytic changes, sclerosis, periosteal bone formation, sequestration and non-healing extraction sockets were scored as: absent (0), localized/single (1) and extensive/multiple (2). Each one of other findings were scored individually as: absent (0) and present (1). For statistical analysis t-test, Pearson's r correlation coefficient, one-way ANOVA and Bonferonni were performed., Results: Extensive lytic changes were the most common finding, especially for ORN, where it occurred in all CBCT scans (100%). The mean value of the CRIm index differs significantly between CBCT scans with MRONJ and JM, as well as between those with OM and JM (Bonferroni p < 0.001)., Conclusions: The new modified Composite Radiographic Index introduced in this study, appears to have improved an objective approach to the previously used Composite Radiographic Index by means of cumulative radiologic features. Τhe predominance of certain radiologic features in one or more of these entities may lead the diagnostician towards the correct diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A 74-year-old woman had a mastectomy for right breast cancer in 201X. Eight years later, the patient developed multiple bone metastases and was treated with denosumab by her previous doctor. A year after, she was diagnosed with anti-resorptive agents-related osteonecrosis of the jaw, and preservation treatment was performed. In 201X+11, the patient had difficulty walking and was admitted to our palliative care ward. A month later, her maxillary bone detached extensively and spontaneously. By applying infection preventive measures and in cooperation with the former doctor, dentist, and oral surgeon, as well as visiting the dental department in our hospital, the patient managed to continue eating what she liked. Jaw infection did not occur. The patient died of liver dysfunction due to liver metastasis 5 months following the extensive loss of the maxillary bone.

Avascular necrosis (AVN) involves ischemic cell death of the bone. AVN leaves an abundance of necrotic lipids and debris in the bone marrow, which instigates inflammatory bone repair. Consequently, the necrotic bone microenvironment stimulates excessive bone resorption, leading to joint deformities and osteoarthritis. Here, we performed a detergent-assisted bone wash using poloxamer 407 (P407) to clean the necrotic bone environment by removing lipids and necrotic debris. The new concept was tested using an established ex vivo AVN model of porcine cadaver humeral heads. The P407 wash was performed using P407 solution and followed with saline via two intraosseous needles. Visual inspection and image analyses of average pixel light intensity showed that the P407 wash produced a better-cleaned bone than the saline wash. Analyses of the collected bone wash solution showed a two-fold increase in triglycerides (101 vs. 53 mmol/head, p = 0.006) and a 10-fold increase in the dry weight of the removed debris (1.34 vs. 0.13 g/head, p = 0.02) with the P407 wash compared to saline. The histological evaluation showed significantly decreased Oil-Red-O (fats) staining in the P407-washed bone compared with the saline-washed bone. The in vitro assays of Alizarin red and qPCR showed the P407 wash neither altered the osteogenic behaviors of porcine bone marrow-derived mesenchymal cells (pBMMCs) nor raised inflammatory responses of porcine bone marrow-derived macrophages (pBMMs). In conclusion, detergent-assisted bone wash using P407 produced a better removal of nonsoluble debris from the bone marrow space than the saline wash without causing changes to osteogenesis or inflammatory reactions., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Osteonecrosis of the femoral head (ONFH), a progressive pathological process of femoral head ischemia and osteocyte necrosis, is a refractory orthopedic disease caused by multiple etiologies and there is no complete cure at present. With the extension of ONFH duration, osteocyte apoptosis and trabecular bone loss can decrease the load-bearing capacity of the femoral head, which leads to the collapse of the articular cartilage and subchondral bone. Therefore, an urgent clinical need exists to develop effective treatment strategies of early-stage ONFH for maintaining the hip joint function and preventing femoral head collapse. In recent years, extensive attention has been paid to the application of diverse biomaterials in treating early ONFH for sustaining the normal morphology and function of the autologous femoral head, and slowing disease progression. Herein, we review the research progress of bone grafts, metallic materials, bioceramics, bioglasses and polymer materials for early ONFH treatment, and discuss the biological mechanisms of bone repair and regeneration in the femoral-head necrotic area. We propose suggestions for future research directions, from a special perspective of improving the local microenvironment in femoral head by facilitating vessel-associated osteoclasts (VAOs) generation and coupling of bone-specific angiogenesis and osteogenesis, as well as inhibiting bone-associated osteoclasts (BAOs) and BAO-mediated bone resorption. This review can provide ideas for the research, development, and clinical application of biomaterials for treating early ONFH. STATEMENT OF SIGNIFICANCE: We believe that at least three aspects of this manuscript make it interesting to readers of the Acta Biomaterialia. First, we briefly summarize the incidence, pathogenesis, risk factors, classification criteria and treatment of early osteonecrosis of the femoral head (ONFH). Second, we review the research progress in biomaterials for early ONFH treatment and the biological mechanisms of bone repair and regeneration in femoral-head necrotic area. Third, we propose future research progress on improving the local microenvironment in femoral head by facilitating vessel-associated osteoclasts generation and coupling of bone-specific angiogenesis and osteogenesis, as well as inhibiting bone-associated osteoclasts and bone resorption. We hope this review can provide ideas for the research, development, and clinical application of biomaterials for treating early ONFH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In this case report, a 68-year-old woman, with known insulin-dependent diabetes and myelomatosis, presented with ear pain in her right ear. Otomicroscopy showed exposed bone in the external auditory canal. The patient was examined with wound swab, biopsies, MRI and PET-CT scans to rule out necrotizing external otitis, cholesteatoma and malignancy. Later, the patient's bisphosphonate treatment for myelomatosis was suspected, because osteonecrosis of the external auditory canal is a rare side effect to this treatment. The bone lesion improved after local debridement and cessation of the bisphosphonate treatment.

Müller-Weiss disease (MWD) is the result of a dysplasia of the tarsal navicular bone. Over the adult years, the dysplastic bone leads to the development of an asymmetric talonavicular arthritis with the talar head shifting laterally and plantarly, thus driving the subtalar joint into varus. From a diagnostic point of view, the condition may be difficult to differentiate from an avascular necrosis or even a stress fracture of the navicular, but fragmentation is the result of a mechanical impairment rather than a biological dysfunction.Standardized weight-bearing radiographs (anteroposterior and lateral views) of both feet are usually enough to diagnose MWD. Other imaging modalities such as multi-detector computed tomography and magnetic resonance imaging in early cases for the differential diagnosis can add additional details on the amount of cartilage affected, bone stock, fragmentation, and associated soft tissue injuries. Failure to identify patients with paradoxical flatfeet varus may lead to an incorrect diagnosis and management. Conservative treatment with the use of rigid insoles is effective in most patients. A calcaneal osteotomy seems to be a satisfactory treatment for patients who fail to respond to conservative measures and a good alternative to the different types of peri-navicular fusions. Weight-bearing radiographs are also useful to identify postoperative changes., Competing Interests: None declared., (Thieme. All rights reserved.)

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) is a serious complication of glucocorticoid treatment and is characterized by dysfunctional bone reconstruction at necrotic sites. Our previous study confirmed the protective potential of necrostatin-1, a selective blocker of necroptosis, in glucocorticoid-induced osteoporosis. In this study, rat models of GC-induced ONFH were established to evaluate the effects of necrostatin-1 on osteonecrotic changes and repair processes. Osteonecrosis was verified by histopathological staining. An analysis of trabecular bone architecture was performed to evaluate osteogenesis in the osteonecrotic zone. Then, necroptotic signaling molecules such as RIP1 and RIP3 were examined by immunohistochemistry. Histopathological observations indicated that necrostatin-1 administration reduced the incidence of osteonecrosis and the osteogenic response in subchondral areas. Additionally, bone histomorphometry demonstrated that necrostatin-1 intervention could restore bone reconstruction in the necrotic zone. The protective mechanism of necrostatin-1 was related to the inhibition of RIP1 and RIP3. Necrostatin-1 administration alleviated GC-induced ONFH in rats by attenuating the formation of necrotic lesions, recovering the function of osteogenesis, and suppressing glucocorticoid-induced osteocytic necroptosis by inhibiting the expression of RIP1 and RIP3., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

This study aimed to explore the mechanism of alcohol-induced Osteonecrosis of the femoral head (ONFH) through in vivo and in vitro experiments. In vitro, the Oil Red O staining showed that ethanol promoted extracellular adipogenesis in a dose-dependent manner. ALP staining and alizarin red staining showed that ethanol inhibited the formation of extracellular mineralization in a dose-dependent manner. The Oil Red O staining showed that miR122 mimics and Lnc-HOTAIR SiRNA rescued extracellular adipogenesis induced by ethanol in BMSCs. Besides, we found that the high expression of PPARγ in BMSCs recruited histone deacetylase 3 (HDAC3) and histone methyltransferase (SUV39H1), which reduced the histone acetylation level and increased the histone methylation level in the miR122 promoter region, respectively. In vivo, the levels of H3K9ac, H3K14ac, and H3K27ac of miR122 promoter region in the ethanol group were significantly decreased compared to the control group, respectively. The levels of H3K9me2 and H3K9me3 of miR122 promoter region in the ethanol group were significantly increased compared to the control group. Lnc-HOTAIR/miR-122/PPARγ signaling mediated the alcohol-induced ONFH in the rat model. Furthermore, the persistent decrease of miR122 expression mediated the continuous progress of alcohol-induced ONFH after stopping alcohol consumption., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Non-traumatic osteonecrosis of the femoral head (ONFH) relies on multiple pathogenic factors, including intravascular coagulation, osteoporosis and lipid metabolism disorders. Despite extensively explored from various aspects, genetic mechanism underlying non-traumatic ONFH has not been fully elucidated. We randomly collected blood and necrotic tissue samples from 32 patients with non-traumatic ONFH as well as blood samples from 30 healthy individuals for whole exome sequencing (WES). Germline mutation and somatic mutation were analyzed to identify new potential pathogenic genes responsible for non-traumatic ONFH. Three genes might correlate with non-traumatic ONFH: VWF, MPRIP (germline mutations) and FGA (somatic mutations). Germline or somatic mutations in VWF, MPRIP and FGA correlate with intravascular coagulation, thrombosis, and consequently, ischemic necrosis of the femoral head., (© 2023. The Author(s).)

Background: Mueller-Weiss disease, a rare and complex foot condition, is defined as spontaneous and progressive navicular fragmentation leading to midfoot pain and deformity. However, its exact etiopathogenesis remains unclear. We report a case series of tarsal navicular osteonecrosis to describe the clinical and imaging characteristics and etiologic profile of the disease., Methods: This retrospective study included five women diagnosed as having tarsal navicular osteonecrosis. The following data were extracted from medical records: age, comorbidities, alcohol and tobacco consumption, history of trauma, clinical presentation, imaging modalities performed, treatment protocol, and outcomes., Results: Five women with a mean age of 51.4 years (range, 39-68 years) were enrolled in the study. Mechanical pain and deformity over the dorsum of the midfoot was the main clinical presentation. Rheumatoid arthritis, granulomatosis with polyangiitis, and spondyloarthritis were reported by three patients. Radiographs revealed bilateral distribution in one patient. Three patients underwent computed tomography. It showed a fragmentation of the navicular bone in two cases.Magnetic resonance imaging was performed in one patient showing flattening of the lateral aspect of the navicular bone with signal abnormalities. Talonaviculocuneiform arthrodesis was performed in all of the patients., Conclusions: Mueller-Weiss disease-like changes may occur in patients with an underlying inflammatory disease such as rheumatoid arthritis and spondyloarthritis.

Objectives: To investigate the comparison of maximum and mean standardized uptake values (SUVs) of jaw pathologies with bone Single-photon emission computed tomography/computed tomography (SPECT/CT), and a special focus on medication-related osteonecrosis of the jaw (MRONJ)., Methods: Eighty-nine patients with jaw pathologies (63 MRONJ, 13 chronic osteomyelitis, 11 osteoradionecrosis and 2 primary intraosseous carcinoma) underwent bone SPECT/CT scans acquisition at 4 h after intravenous injection of Tc-99m hydroxymethylene diphosphonate in this prospective study. The evaluation of mean and maximum SUVs of jaw pathologies were performed using Q. Metrix and Xeleris workstation and defined the data automatically. Statistical analyses were performed by Pearson's correlation coefficient for comparison of maximum and mean SUVs and Mann-Whitney U-test for SUVs of MRONJ. A P value lower than 0.05 was considered to indicate statistical significance., Results: Maximum SUVs of MRONJ, chronic osteomyelitis, osteoradionecrosis and primary intraosseous carcinoma were 17.6 ± 8.4, 21.7 ± 7.1, 11.9 ± 4.8 and 26.6 ± 7.0, respectively. Mean SUVs of MRONJ, chronic osteomyelitis, osteoradionecrosis and primary intraosseous carcinoma were 10.1 ± 4.9, 11.9 ± 3.3, 7.0 ± 2.8 and 10.1 ± 4.5, respectively. The maximum SUV of jaw pathologies was significantly correlated with the mean SUV (Y = 0.494X + 1.228; R2 = 0.786; P < 0.001). Furthermore, maximum and mean SUVs of MRONJ had significant differences in underlying diseases, medication and staging., Conclusion: The maximum and mean SUVs with bone SPECT/CT can be an effective tool for the quantitative evaluation of jaw pathologies, especially MRONJ., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Spontaneous osteonecrosis of the knee (SONK) is the most common phenotype of osteonecrosis of knee joints in older adults. Early diagnosis with appropriate management is crucial for improving the prognosis of the SONK. We present SONK in bone scintigraphy and SPECT/CT in 65-year-old man with sudden worsening knee pain and normal radiographs. SPECT/CT revealed intense uptake in subchondral area of left femoral medial condyle, which can be differed from progressed osteoarthritic change of the knee joints suspected on planar scintigraphy. Subsequently performed MRI showed characteristic finding of SONK. Total knee replacement arthroplasty was performed with final histological diagnosis of SONK., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no conflicts of interest. This research was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (2021R1A2C1093636, H.-J.Y.; 2021R1F1A1060946, B.S.K.)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Glucocorticoids (GCs) are widely used in various autoimmune diseases. Side effects may occur in patients with long-term or high-dose GC usage. Among them, steroid myopathy and osteonecrosis are two severe forms. We report a patient with pemphigus vulgaris on GC-treatment who developed muscle weakness when a cumulative dose of methylprednisolone reached about 20g (14-80mg/d for 2.5 years). Laboratory tests showed slightly elevated lactate dehydrogenase and hydroxybutyrate dehydrogenase. MRI revealed osteonecrosis in the femoral head, distal femur, and proximal tibia of both legs. The biopsy of the right quadriceps revealed atrophy of type II myofiber without leukocyte infiltration, which was suggestive of steroid myopathy. Genotyping of the patient showed 5G/5G genotype of the PAI-1 gene and CC genotype of the ABCB1 gene (C3435T), suggesting she was sensitive to GCs. The patient's lesions were considered to be GC-induced adverse events, which were improved with tapering GC. Therefore, it is important to recognize steroid-induced musculoskeletal side effects and genotyping favors personalized medication., 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 © 2022 Hu, Lu and Lin.)

Aim: The purpose of this study was to investigate the functions of exosomal miR-150 derived from bone marrow mesenchymal stem cells in osteonecrosis of the femoral head (ONFH). Materials & methods: Cell viability and apoptosis were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. Alizarin red staining was performed to detect calcium deposits. A rat model was established to assess the effects of exosomal miR-150 on ONFH in vivo . Results: Exosomes or exosomal miR-150 derived from bone marrow mesenchymal stem cells inhibited TNF-α-induced osteoblast apoptosis and promoted osteogenic differentiation and autophagy. Exosomal miR-150 suppressed apoptosis and induced autophagy in TNF-α-treated osteoblasts by regulating the GREM1/NF-κB axis. Exosomal miR-150 also improved the pathological features of ONFH in vivo . Conclusion: Exosomal miR-150 alleviates ONFH by mediating the GREM1/NF-κB axis. This study provides a potential therapeutic strategy for ONFH.

Objectives: The objective of this study is to evaluate the relationship between the radiological features of periosteal reactions (PR) and histopathological features of the lesions., Methods: A total of 4605 CBCT images were evaluated and they were classified according to their radiological differential diagnosis. Images with pathologies were listed according to their histopathological examinations as cystic lesions, benign tumours, malignant tumours, fibro-osseous lesions and osteonecrosis, while images without pathologies were listed as traumas and others. All groups were reclassified as with or without the presence of detected PR., Results: Pathologies and traumas were detected in 1801 of 4605 patients. There were 3 PR in 1140 cystic lesions, 4 PR in 102 benign tumours, 16 PR in 43 malignant tumours, 67 PR in 156 osteonecrosis/osteomyelitis cases and 3 PR in 262 trauma cases. As a result of the chi-square test between groups, there was a significant relationship between histopathologic diagnoses and periosteal reaction patterns (p = 0.000)., Conclusions: Although there is a significant overlap between the patterns of PRs, PRs can be used to narrow the possibilities in the differential diagnosis. However, PRs alone are not sufficient variables for differential diagnosis in the absence of cortical bone destruction, localization, clinical and systemic findings., (© 2021. The Author(s) under exclusive licence to Japanese Society for Oral and Maxillofacial Radiology.)

Subchondral insufficiency fracture of the knee (SIFK) is a common cause of knee joint pain in older adults. SIFK is a type of stress fracture that occurs when repetitive and excessive stress is applied to the subchondral bone. If the fracture does not heal, the lesion develops into osteonecrosis and results in osteochondral collapse, requiring surgical management. Because of these clinical features, SIFK was initially termed "spontaneous osteonecrosis of the knee (SONK)" in the pre-MRI era. SONK is now categorized as an advanced SIFK lesion in the spectrum of this disease, and some authors believe the term "SONK" is a misnomer. MRI plays a significant role in the early diagnosis of SIFK. A subchondral T2 hypointense line of the affected condyle with extended bone marrow edema-like signal intensity are characteristic findings on MRI. The large lesion size and the presence of osteochondral collapse on imaging are associated with an increased risk of osteoarthritis. However, bone marrow edema-like signal intensity and osteochondral collapse alone are not specific to SIFK, and other osteochondral lesions, including avascular necrosis, osteochondral dissecans, and osteoarthritis should be considered. Chondral lesions and meniscal abnormalities, including posterior root tears, are also found in many patients with SIFK, and they are considered to be related to the development of SIFK. We review the clinical and imaging findings, including the anatomy and terminology history of SIFK, as well as its differential diagnoses. Radiologists should be familiar with these imaging features and clinical presentations for appropriate management., (© 2021. The Author(s).)

Alcohol-induced osteonecrosis of the femoral head (ONFH) is a disabling disease with a high incidence and elusive pathogenesis. Here, we used single-cell RNA sequencing to explore the transcriptomic landscape of mid- and advanced-stage alcohol-induced ONFH. Cells derived from age-matched hip osteoarthritis and femoral neck fracture samples were used as control. Our bioinformatics analysis revealed the disorder of osteogenic-adipogenic differentiation of stromal cells in ONFH and altered regulons such as MEF2C and JUND. In addition, we reported that one of the endothelial cell clusters with ACKR1 expression exhibited strong chemotaxis and a weak angiogenic ability and expanded with disease progression. Furthermore, ligand-receptor-based cell-cell interaction analysis indicated that ACKR1+ endothelial cells might specifically communicate with stromal cells through the VISFATIN and SELE pathways, thus influencing stromal cell differentiation in ONFH. Overall, our data revealed single cell transcriptome characteristics in alcohol-induced ONFH, which may contribute to the further investigation of ONFH pathogenesis., (© 2022. The Author(s).)

Osteonecrosis of the femoral head (ONFH) is a debilitating disease that is closely associated with the clinical application of high-dose glucocorticoids. Elevated oxidative stress contributes to the pathophysiological changes observed in ONFH. The lack of effective treatments besides surgical intervention highlights the importance of finding novel therapeutics. Our previous studies demonstrated that D7, a cyclic polypeptide, enhances the adhesion, expansion, and proliferation of bone marrow mesenchymal stem cells (BMSCs). Therefore, in this study, we investigated the therapeutic effects of D7 against ONFH in BMSCs and evaluated the underlying mechanisms. First, we screened for ONFH risk factors. Then, we applied D7 treatment to steroid-induced ONFH (SONFH) in an in vitro model produced by dexamethasone (DEX) to further elucidate the underlying mechanisms. We found negative correlations among oxidative stress marker expression, growth differentiation factor 15 (GDF15) levels, and ONFH. Furthermore, we demonstrated that DEX inhibited the proliferation and induced apoptosis of BMSCs by suppressing GDF15/AKT/mammalian target of rapamycin (mTOR) signaling. D7 alleviated DEX-induced BMSCs injury and restored the chondrogenic function of BMSCs by activating GDF15/AKT/mTOR signaling. In addition, DEX-induced excessive reactive oxygen species (ROS) generation was an upstream trigger of GDF15-mediated signaling, and D7 ameliorated this DEX-induced redox imbalance by restoring the expression of antioxidants, including superoxide dismutase (SOD) 1, SOD2, and catalase, via regulation of GDF15 expression. In conclusion, our findings revealed the potential therapeutic effects of D7 in SONFH and showed that this protective function may be mediated via inhibition of DEX-induced ROS and activation of GDF15/AKT/mTOR signaling, thereby providing insights into the potential applications of D7 in SONFH treatment., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Jiazheng Chen et al.)

Osteonecrosis of the jaws (ONJ) usually has a clear etiology. Local infection or trauma, radiotherapy and drugs that disrupt the vascular supply or bone turnover in the jaws are its major contributors. The thrombotic occlusion of the bone's venous outflow that occurs in individuals with hereditary thrombophilia and/or hypofibrinolysis has a less known impact on jaw health and healing capability. Our research provides the most comprehensive, up-to-date and systematized information on the prevalence and significance of hereditary thrombophilia and/or hypofibrinolysis states in ONJ. We found that hereditary prothrombotic abnormalities are common in patients with ONJ refractory to conventional medical and dental treatments. Thrombophilia traits usually coexist with hypofibrinolysis traits. We also found that frequently acquired prothrombotic abnormalities coexist with hereditary ones and enhance their negative effect on the bone. Therefore, we recommend a personalized therapeutic approach that addresses, in particular, the modifiable risk factors of ONJ. Patients will have clear benefits, as they will be relieved of persistent pain and repeated dental procedures.

Background: The effectiveness and availability of conservative therapies for osteonecrosis of the femoral head (ONFH) are limited. Transplantation of bone marrow mesenchymal stem cells (BMSCs) combined with Bio-Oss, which is a good bone scaffold biomaterial for cell proliferation and differentiation, is a new potential therapy. Of note, the expression of miRNAs was significantly modified in cells cultured with Bio-Oss, and MiR-214 was correlated positively with osteonecrosis. Furthermore, miR-214 was upregulated in cells exposed to Bio-Oss., Objective: To investigate whether targeting miR-214 further improves the transplantation effect., Methods: We treated BMSCs with agomiR-214 (a miR-214 agonist), antagomiR-214 (a miR-214 inhibitor), or vehicle, followed by their transplantation into ONFH model rats., Results: Histological and histomorphometric data showed that bone formation was significantly increased in the experimental groups (Bio-Oss and BMSCs treated with antagomiR-214) compared with other groups., Conclusions: miR-214 participates in the inhibition of osteoblastic bone formation, and the inhibition of miR-214 to bone formation during transplantation therapy with Bio-Oss combined with BMSCs for ONFH.

MicroRNAs (miRNAs) are a class of small (20-24 nucleotides), highly conserved, non-coding RNA molecules whose main function is the post-transcriptional regulation of gene expression through sequence-specific manners, such as mRNA degradation or translational repression. Since these key regulatory molecules are implicated in several biological processes, their altered expression affects the preservation of cellular homeostasis and leads to the development of a wide range of pathologies. Over the last few years, relevant investigations have elucidated that miRNAs participate in different stages of bone growth and development. Moreover, the abnormal expression of these RNA molecules in bone cells and tissues has been significantly associated with the progression of numerous bone diseases, including osteoporosis, osteosarcoma, osteonecrosis and bone metastasis, among others. In fact, miRNAs regulate multiple pathological mechanisms, including altering either osteogenic or osteoblast differentiation, metastasis, osteosarcoma cell proliferation, and bone loss. Therefore, in this present review, aiming to impulse the research arena of the biological implications of miRNA transcriptome in bone diseases and to explore their potentiality as a theragnostic target, we summarize the recent findings associated with the clinical significance of miRNAs in these ailments.

Objective: Review long-term clinical and quality-of-life outcomes following free flap reconstruction for osteonecrosis., Study Design: Retrospective multi-institutional review., Setting: Tertiary care centers., Methods: Patients included those undergoing free flap reconstructions for osteonecrosis of the head and neck (N = 232). Data included demographics, defect, donor site, radiation history, perioperative management, diet status, recurrence rates, and long-term quality-of-life outcomes. Quality-of-life outcomes were measured using the University of Washington Quality of Life (UW-QOL) survey., Results: Overall flap success rate was 91% (n = 212). Relative to preoperative diet, 15% reported improved diet function at 3 months following reconstruction and 26% at 5 years. Osteonecrosis recurred in 14% of patients (32/232); median time to onset was 11 months. Cancer recurrence occurred in 13% of patients (29/232); median time to onset was 34 months. Results from the UW-QOL questionnaire were as follows: no pain (45%), minor or no change in appearance (69%), return to baseline endurance level (37%), no limitations in recreation (40%), no changes in swallowing following reconstruction (28%), minor or no limitations in mastication (29%), minor or no speech difficulties (93%), no changes in shoulder function (84%), normal taste function (19%), normal saliva production (27%), generally excellent mood (44%), and no or minimal anxiety about cancer (94%)., Conclusion: The majority of patients maintained or had advancement in diet following reconstruction, with low rates of osteonecrosis or cancer recurrence and above-average scores on UW-QOL survey suggesting good return of function and quality of life.

An important objective of vascularized tissue regeneration is to develop agents for osteonecrosis. We aimed to identify the pro-angiogenic and osteogenic efficacy of adipose tissue-derived (AD) pericytes combined with Nel-like protein-1 (NELL-1) to investigate the therapeutic effects on osteonecrosis. Tube formation and cell migration were assessed to determine the pro-angiogenic efficacy. Vessel formation was evaluated in vivo using the chorioallantoic membrane assay. A mouse model with a 2.5 mm necrotic bone fragment in the femoral shaft was used as a substitute for osteonecrosis in humans. Bone formation was assessed radiographically (plain radiographs, three-dimensional images, and quantitative analyses), and histomorphometric analyses were performed. To identify factors related to the effects of NELL-1, analysis using microarrays, qRT-PCR, and Western blotting was performed. The results for pro-angiogenic efficacy evaluation identified synergistic effects of pericytes and NELL-1 on tube formation, cell migration, and vessel formation. For osteogenic efficacy analysis, the mouse model for osteonecrosis was treated in combination with pericytes and NELL-1, and the results showed maximum bone formation using radiographic images and quantitative analyses, compared with other treatment groups and showed robust bone and vessel formation using histomorphometric analysis. We identified an association between FGF2 and the effects of NELL-1 using array-based analysis. Thus, combinatorial therapy using AD pericytes and NELL-1 may have potential as a novel treatment for osteonecrosis.

Background: The number of articles of clinical and basic research for osteonecrosis of the femoral head (ONFH) is increasing, yet, to our knowledge, there is still a lack of bibliometric analysis on ONFH articles. The purpose of this study was to identify the top 100 cited (T100) articles related to ONFH research and to analyze the characteristics and qualities of these articles., Methods: The T100 articles on ONFH were retrieved from the Web of Science database. The information about each article including citations, titles, authors, journals, countries, institutions, and keywords was recorded for bibliometric analysis., Results: The T100 articles related to ONFH were mainly published from 1991 to 2010 ( n = 70) and were originated from 24 countries. The USA, China, and Japan were the most productive countries in this regard. The most prolific institution was the University of Pennsylvania from the USA with 6 publications and 742 citations. The most cited article was published in 1995 by Professor Steinberg ME. The five most frequently occurring keywords were "femoral head," "osteonecrosis," "core decompression," "total hip arthroplasty," and "follow up." The keywords like "bone tissue engineering" and "extracorporeal shock wave" have emerged in recent years., Conclusions: The USA, China, and Japan contributed greatly in terms of the T100 articles. The outcomes of core decompression and total hip arthroplasty gathered the most research interests. In recent years, bone tissue engineering and extracorporeal shock wave have become new trends. However, the mechanism of ONFH is still unclear., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2021 Yumin Zhang et al.)

Purpose: The application of the anatomical parameters of the contralateral hip joint to guide the preoperative template of the affected side relies on the bilateral hip symmetry. We investigated the bilateral hip symmetry and range of anatomical variations by measurement and comparison of bilateral hip anatomical parameters., Methods: This study included 224 patients (448 hips) who were diagnosed with osteoarthritis (OA) and avascular necrosis (AVN) of the femur head, and underwent bilateral primary total hip arthroplasty (THA) in our hospital from January 2012 to August 2020. Imaging data included 224 patients X-ray and 30 CT data at the end of the cohort. Anatomical parameters, including the acetabular abduction angle and trochanteric height, were measured using the Noble method. Postoperative measurements included stem size, difference of leg length and offset., Results: Except for the isthmus width, there were no significant differences in the anatomical morphology of the hip joint. Among the demographic factors, there was a correlation between body weight and NSA. Among various anatomical parameters, a correlation was present between medullary cavity widths of T + 20, T, and T - 20. The difference in the use of stem size is not due to the morphological difference of bilateral medullary cavity, but due to the different of 1- or 2-stage surgery., Conclusion: Bilateral symmetry was present among the patients with normal morphology of the hip medullary cavity, theoretically confirming the feasibility of structural reconstruction of the hip joint using the hip joint on the uninjured side. Additionally, the difference in the morphology of the hip medullary cavity is not present in a single plane but is synergistically affected by multiple adjacent planes., (© 2021. The Author(s).)

This study aimed to evaluate the efficacy and safety of bone cement-augmented pedicle screw fixation for stage III Kümmell disease. Twenty-five patients with stage III Kümmell disease who received bone cement-augmented pedicle screw fixation at the First Affiliated Hospital of Guangzhou University of Chinese Medicine between June 2009 and December 2015 were enrolled. All patients were females with a history of osteoporosis. The vertebral Cobb angle (V-Cobb angle), the fixed segment Cobb Angle (S-Cobb angle), pelvic parameters, visual Analogue Scale (VAS) score, and Oswestry Disability Index (ODI) were assessed preoperatively, postoperatively and at the final follow-up. Complications, loosening rate, operation time, and intraoperative bleeding were recorded. The average lumbar vertebral density T-value was - 3.68 ± 0.71 SD, and the average age was 71.84 ± 5.39. The V-Cobb angle, S-Cobb angle, and Sagittal Vertical Axis (SVA) were significantly smaller postoperatively compared to the preoperative values. The VAS and ODI at 1 month after surgery were 3.60 ± 1.00 and 36.04 ± 6.12%, respectively, which were both significantly lower than before surgery (VAS: 8.56 ± 1.04, ODI: 77.80 ± 6.57%). Bone cement-augmented pedicle screw fixation is a safe and effective treatment for stage III Kümmell disease. It can effectively correct kyphosis, restore and maintain sagittal balance, and maintain spinal stability.

Non-traumatic osteonecrosis of the femoral head (ONFH) usually affects adults younger than 50 years and frequently leads to femoral head collapse and subsequent arthritis of the hip. It is becoming more prevalent along with increasing use of corticosteroids for the adjuvant therapy of leukemia and other myelogenous diseases as well as management of organ transplantation. This review updated knowledge on the pathogenesis, classification criteria, staging system, and treatment of ONFH., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common orthopaedic disease. GIONFH primarily manifests clinically as hip pain in the early stages, followed by the collapse of the femoral head, narrowing of the hip joint space and damage to the acetabulum, resulting in severely impaired mobility. However, the pathogenesis of GIONFH is not clearly understood. Recently, biomechanical forces and non-coding RNAs have been suggested to play important roles in the pathogenesis of GIONFH. This study aimed to evaluate the role of biomechanical forced and non-coding RNAs in GIONFH. We utilized an in vivo, rat model of GIONFH and used MRI, μCT, GIONFH-TST (tail suspension test), GIONFH-treadmill, haematoxylin and eosin staining, qRT-PCR and Western blot analysis to analyse the roles of biomechanical forces and non-coding RNAs in GIONFH. We used RAW264.7 cells and MC3T3E1 cells to verify the role of MALAT1/miR-329-5p/PRIP signalling using a dual luciferase reporter assay, qRT-PCR and Western blot analysis. The results demonstrated that MALAT1 and PRIP were up-regulated in the femoral head tissues of GIONFH rats, RAW264.7 cells, and MC3T3E1 cells exposed to dexamethasone (Dex). Knockdown of MALAT1 decreased PRIP expression in rats and cultured cells and rescued glucocorticoid-induced osteonecrosis of femoral head in rats. The dual luciferase reporter gene assay revealed a targeting relationship for MALAT1/miR-329-5p and miR-329-5p/PRIP in MC3T3E1 and RAW264.7 cells. In conclusion, MALAT1 played a vital role in the pathogenesis of GIONFH by binding to ('sponging') miR-329-5p to up-regulate PRIP. Also, biomechanical forces aggravated the pathogenesis of GIONFH through MALAT1/miR-329-5p/PRIP signalling., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Glucocorticoids (GCs) are used in treating viral infections, acute spinal cord injury, autoimmune diseases, and shock. Several patients develop GC-induced osteonecrosis of the femoral head (ONFH). However, the pathogenic mechanisms underlying GC-induced ONFH remain poorly understood. GC-directed bone marrow mesenchymal stem cells (BMSCs) fate is an important factor that determines GC-induced ONFH. At high concentrations, GCs induce BMSC apoptosis by promoting oxidative stress. In the present study, we aimed to elucidate the molecular mechanisms that relieve GC-induced oxidative stress in BMSCs, which would be vital for treating ONFH. The endocannabinoid system regulates oxidative stress in multiple organs. Here, we found that monoacylglycerol lipase (MAGL), a key molecule in the endocannabinoid system, was significantly upregulated during GC treatment in osteoblasts both in vitro and in vivo. MAGL expression was positively correlated with expression of the NADPH oxidase family and apoptosis-related proteins. Functional analysis showed that MAGL inhibition markedly reduced oxidative stress and partially rescued BMSC apoptosis. Additionally, in vivo studies indicated that MAGL inhibition effectively attenuated GC-induced ONFH. Pathway analysis showed that MAGL inhibition regulated oxidative stress in BMSCs via the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The expression of Nrf2, a major regulator of intracellular antioxidants, was upregulated by inhibiting MAGL. Nrf2 activation can mimic the effect of MAGL inhibition and significantly reduce GC-induced oxidative damage in BMSCs. The beneficial effects of MAGL inhibition were attenuated after the blockade of the Keap1/Nrf2 antioxidant signaling pathway. Notably, pharmacological blockade of MAGL conferred femoral head protection in GC-induced ONFH, even after oxidative stress responses were initiated. Therefore, MAGL may represent a novel target for the prevention and treatment of GC-induced ONFH., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Steroid‑induced avascular necrosis of the femoral head (SANFH) is a common orthopaedic disease that is difficult to treat. The present study investigated the effects of total flavonoids of Rhizoma drynariae (TFRD) on SANFH and explored its underlying mechanisms. The SANFH rat model was induced by intramuscular injection of lipopolysaccharides and methylprednisolone. Osteoblasts were isolated from the calvariae of neonatal rats and then cultured with dexamethasone (Dex). TFRD was used in vitro and in vivo , respectively. Haematoxylin and eosin staining was used to assess the pathological changes in the femoral head. Terminal deoxynucleotidyl transferase‑mediated deoxyuridine triphosphate nick end labelling assay and flow cytometry were conducted to detect apoptosis of osteoblasts. The 2',7'‑dichlorofluorescein‑diacetate staining method was used to detect reactive oxygen species (ROS) levels in osteoblasts and the 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay was used to detect osteoblast proliferation. The expression of caspase‑3, Bax, Bcl‑2, VEGF, runt‑related transcription factor 2 (RUNX2), osteoprotegerin (OPG), osteocalcin (OCN), receptor activator of nuclear factor κB ligand (RANKL) and phosphoinositide 3‑kinase (PI3K)/AKT pathway related‑proteins were detected via western blotting. It was found that TFRD reduced the pathological changes, inhibited apoptosis, increased the expression of VEGF, RUNX2, OPG and OCN, decreased RANKL expression and activated the PI3K/AKT pathway in SANFH rats. TFRD promoted proliferation, inhibited apoptosis and reduced ROS levels by activating the PI3K/AKT pathway in osteoblasts. In conclusion, TFRD protected against SANFH in a rat model. In addition, TFRD protected osteoblasts from Dex‑induced damage through the PI3K/AKT pathway. The findings of the present study may contribute to find an effective treatment for the management of SANFH.