Hemiarthroplasty consists of the replacement of local cartilage defects by a partial implant and provides a less aggressive alternative to total joint replacement. The material frequently selected nowadays for partial implants is CoCrMo alloy, which results in a sliding contact between articular cartilage and the alloy. Since the geometry of the implant needs to be tailored to the patient, partial implant technology would greatly profit from novel additive manufacturing techniques. This study examines the feasibility of using additive manufacturing techniques on partial implants made of CoCrMo alloys, with a particular focus on the impact of manufacturing technique on mechanical stimulation, cartilage analysis, and friction performance. To this end, in vitro biotribological experiments were performed between CoCrMo samples and bovine articular cartilage using PBS as simulated body fluid. Key findings reveal significant changes in microstructure between laser beam melted (LBM) and wrought CoCrMo alloys, despite having a comparable elemental composition. The coefficient of friction (CoF) measured between bovine articular cartilage and the CoCrMo specimens during biotribocorrosive testing revealed no significant differences resulting from the manufacturing techniques, even though wrought CoCrMo resulted in a higher reproducibility. Conventionally produced CoCrMo also exhibited a more anodic open circuit potential during the experiments, likely due to the significant differences in microstructure that affect corrosion resistance. The tested cartilage samples showed a slight increase in MMP13 (Matrix Metalloproteinases - degradative enzymes) in comparison to the controls, indicating potential remodeling effects, especially for the LBM CoCrMo alloy. Additionally, the metabolic activity in the cartilage specimens increased due to mechanical stimulation. No cracks or fissures were detected in histological imaging thus highlighting that the cartilage samples were not damaged during harvesting or testing. These findings indicate the possibility of an equivalent use of additive manufactured CoCrMo, enabling patient-specific surgeries and encourage further research to explore the long-term impact of corrosion stability on implant longevity and functionality.

Introduction. Bone marrow lesions (BMLs) are MRI-visible subchondral bone alterations, highly correlated with symptoms in the knee. Subchondroplasty (SCP) is able to fill the subchondral defects associated with BMLs using an injectable bone substitute material. The aim of the present study is to evaluate the 12-month outcomes of the SCP in the treatment of symptoms of mild-to-moderate knee osteoarthritis (OA) patients with persistent BMLs of the knee. Materials and Methods. Subjects affected by BMLs of the femoral condyle or tibial plateau that were present for >3 months and not responsive to conservative treatments were enrolled in this prospective multicenter trial. All the patients underwent SCP. Follow-up was conducted at 1, 3, 6 and 12 months. All subjects completed Numerical Rating Scale (NRS) for pain, Knee Injury and Osteoarthritis Outcome (KOOS) score, Euro Quality of life-5 dimensions (EQ-5D) score, and a subject global satisfaction scale. Demographic information of the patients was also collected. Results. A total of 79 patients completed the 12-month follow-up. Statistically significant improvements on all clinical scales were registered from baseline to the 12-month follow-up. No severe adverse events were reported. Four patients were considered failed. A 12-month subgroup analysis was performed to evaluate the possible correlation between all the KOOS subscales and age, gender, number of BMLs, location of BMLs, and Kellgren-Lawrence grade: no statistically significant associations were observed. Conclusion. SCP is a safe and effective procedure for the treatment of symptoms related to persisting BMLs in mild-to-moderate osteoarthritic knees, with a low failure rate up to 12 months' evaluation.

α-Solanine, a glycoalkaloid (GA) extracted from the stems of the potato plant, exhibits bioactivity and medicinal potential that necessitate further investigation. The impact and underlying mechanisms of α-Solanine on osteoarthritis (OA) remain to be elucidated. To achieve enhanced therapeutic outcomes, we have designed and synthesized a UIO-66-NH2@α-Solanine@PEI charged particle (USP) that amplifies the therapeutic effects of α-Solanine, demonstrating superior efficacy. Our approach involved the synthesis of a novel drug delivery system, the USP, to augment the therapeutic potential of α-Solanine in the treatment of OA. An OA rat model was established, and USP treatment was administered. The therapeutic effects were verified through histochemical staining and micro-CT. In vitro, α-Solanine significantly suppressed the expression of proteins related to glycolysis and notably inhibited ferroptosis. RNA sequencing revealed hypoxia-inducible factor-1α (HIF-1α) as a potential pathway mediating the effects of α-Solanine, and it was found that the co-addition of cycloheximide (CHX) led to a shortened decay time of HIF-1α. In vivo, rats with OA demonstrated significant inhibition of glycolysis and ferroptosis following treatment with USP, along with improvements in OA characteristics. These findings suggest that α-Solanine can inhibit the intense glycolysis associated with OA via the HIF-1α pathway and alleviate ferroptosis in chondrocytes. Treatment with USP demonstrated superior efficacy in the management of OA, providing a new therapeutic strategy for the disease.

Osteoarthritis (OA) is a chronic and degenerative joint disease with a rising incidence worldwide. Current therapeutic approaches primarily focus on symptom relief through systemic administration, which raises safety concerns related to side effects and long-term use. In this context, the local administration of natural compounds with anti-inflammatory and anti-arthritic properties, such as β-Lapachone constitutes an interesting alternative. In this work, we prepared and characterized injectable thermosensitive hybrid hydrogels loaded with β-Lapachone. A comprehensive characterization of the hydrogel systems was performed, including micellar diameter, mechanical properties at different temperatures, the ability to control drug release and microstructure. The anti-inflammatory activity of the free drug, as well as that of the blank or loaded hydrogels was then evaluated ex vivo, using OA cartilage explants. Additionally, in vivo studies were carried out in a rabbit model of OA to assess their clinical potential. The results suggest that the hydrogel systems possess a composite microstructure integrating micelles, together with a temperature-responsive stiffness and the ability to modulate drug release. In addition, β-Lapachone-loaded hydrogels display an interesting immunomodulatory potential ex vivo, as they were able to efficiently reduce the secretion of several proinflammatory mediators, such as IL-6, MMP9, MMP13 and CXCL8. Furthermore, the drug-loaded hydrogels were found to improve in vivo cartilage and bone histomorphometric markers, such as subchondral bone thickness, as well as early signs of cartilage damage, such as the fibrillation index. Therefore, the developed β-Lapachone-loaded thermosensitive hydrogels constitute a promising alternative for OA management.

Osteoarthritis (OA) is a complex disorder driven by the combination of environmental and genetic factors. Given its high global prevalence and heterogeneity, developing effective and personalized treatment methods is crucial. This requires identifying new disease mechanisms, drug targets, and biomarkers. Various omics approaches have been applied to identify OA-related genes, pathways, and biomarkers, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics. These omics studies have generated vast datasets that are shaping the field of OA research. The emergence of high-resolution methodologies, such as single-cell and spatial omics techniques, further enhances our ability to dissect molecular complexities within the OA microenvironment. By integrating these multi-layered datasets, researchers can uncover central signaling hubs and disease mechanisms, ultimately facilitating the development of targeted therapies and precision medicine approaches for OA treatment.

The complex nature of osteoarthritis (OA), driven by the intricate interplay of genetic, environmental, and lifestyle factors, necessitates the development of a single treatment method, which is highly challenging. The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids often leads to adverse side effects like kidney damage and stomach ulcers. Major health threats like obesity and aging create a milieu of chronic low-grade inflammation and increased mechanical stress on the joints resulting in cartilage deterioration. Additionally, postmenopausal women with lower circulating 17β-estradiol levels experience accelerated joint deterioration due to increased immune activity resulting in the increased production of pro-inflammatory cytokines, with elevated MMP expression and decreased type II collagen synthesis. Polyphenols are nature's gifted magic molecules, which possess diverse biological properties like anti-oxidant, anti-bacterial, anti-inflammatory, estrogenic, and insulin-sensitizing effects, which can manage and treat all the multi-factorial contributing factors of OA effectively. Certain polyphenols can act as phytoestrogens and mimic the effects of natural estrogen by binding to ERα and ERβ and can act as SERMs and prevent degradation of the articular cartilage thereby alleviating osteoarthritic conditions. These molecules downregulate the expression of various pro-inflammatory cytokines, apoptotic genes, and matrix-degrading proteases (MMPs) while upregulating major ECM proteins like type II collagen, aggrecan, and proteoglycans in various osteoarthritic animal models. This review provides a comprehensive overview of the molecular mechanisms involved in OA development and also explores the therapeutic potential of different polyphenols in mitigating joint inflammation and their protective effect in inhibiting the degradation of cartilage extracellular matrix (ECM) and enhancing joint homeostasis.

The endplate region of the vertebra, which includes the bony endplate (BEP) and underlying subchondral trabecular bone (STB), is critically involved in vertebral fracture (VF). While evidence abounds that failure initiates in the endplate region, the relative risk of failure of the BEP vs. STB has not been established. In this study, micro-finite element models were constructed of L1 vertebrae (n = 21) that were mechanically tested in a prior study and given experimentally matched boundary conditions corresponding to the vertebra's yield point. Volumes of interest (VOIs) were defined corresponding to the BEP and STB; the remainder was defined as the mid-vertebral body (MVB). The proportion of elements within each VOI that yielded was defined as the VOI yield fraction, and this value divided by the yield fraction of the entire model was defined as the normalized yield fraction. While yield fraction did not differ across VOIs (p = 0.179), normalized yield fraction was greater in the BEP than STB and MVB (p < 0.001), indicating a higher risk of yield in the BEP compared to the other two VOIs. None of the yield fractions was correlated with BEP or STB microstructure, and tension (rather than compression) was the dominant mode of tissue level yield. These findings indicate that the BEP, more so than the STB, is likely the site of VF initiation and that current methods of screening for VF risk, because they omit specific analysis of the BEP, are missing the region that matters the most. The endplate region of the vertebra, which includes the bony endplate (BEP) and underlying subchondral bone (SB), is critically involved in vertebral fracture (VF). While evidence abounds that failure initiates in the endplate region, the relative risk of failure of the BEP vs. SB has not been established. In this study, micro-finite element models were constructed of L1 vertebrae (n = 21) that had been mechanically tested in a prior study, and they were given experimentally matched boundary conditions corresponding to the vertebra's yield point. Volumes of interest (VOIs) were defined corresponding to the BEP and SB; the remainder was defined as the mid-vertebral body (MVB). The proportion of yielded elements within each VOI was defined as the VOI yield fraction, and this value divided by the yield fraction of the entire model was defined as the normalized yield fraction. While yield fraction did not differ across VOIs (p = 0.179), normalized yield fraction was greater in the BEP than SB and MVB (p < 0.001), indicating a higher risk of yield in the BEP compared to the other two VOIs. None of the yield fractions was correlated with BEP or SB microstructure, and tension (rather than compression) was the dominant mode of tissue level yield. These findings indicate that the BEP, more so than the SB, is likely the site of VF initiation and that current methods of screening for VF risk, because they omit specific analysis of the BEP, are missing the region that matters the most.

The asynchronous changes in articular cartilage (AC) and the osteochondral junction (OCJ) in early knee osteoarthritis (KOA) remain controversial, and the utilization of quantitative magnetic resonance imaging (MRI) to investigate the pathogenesis of KOA in vivo has yet to be firmly established. This study investigates the sequential order of pathophysiological changes in the AC and OCJ in early KOA, based on MRI-derived T2 values of the AC and ultrashort echo time (UTE)-T2* values of the OCJ.

3D WATS (three-dimensional water-selective), T2 mapping and UTE-T2* mapping were performed on 34 healthy knees and 42 early osteoarthritis knees. Each knee was divided into medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibial plateau (MTP), lateral tibial plateau (LTP), patellar region and trochlear region. The cartilage T2 and OCJ T2* values were measured in each area. The cartilage from the surface of the cartilage to the tidemark was segmented on 3D WATS images. T2 values were then measured on T2 maps. OCJ was segmented on the UTE subtraction images, and T2* values were obtained from UTE-T2* maps.

The cartilage T2 values were significantly higher in the early KOA group for MFC (P<0.001), MTP (P=0.04), patellar region (P<0.001), and trochlear region (P=0.01) relative to those in the healthy control groups. The OCJ T2* value of KOA group in MFC (P<0.001) showed a significant increase, followed by MTP (P<0.001), LTP (P=0.01), patellar (P=0.03) and trochlear (P=0.01). In the patellar region, the area under the curve (AUC) for diagnosing early KOA using AC T2 values (AUC =0.78, P<0.001) was higher than that using OCJ UTE-T2* values (AUC =0.64, P=0.04). There was a positive correlation between cartilageT2 values and OCJ T2* values (r=0.30, P<0.001).

The T2 and UTE-T2* values, respectively, provide quantitative and non-invasive measures of the degeneration in the AC and the OCJ during the early stages of KOA. Quantitative MRI biomarkers reveal biochemical alterations in both the AC and the OCJ during early KOA, indicating the potential existence of interactions between these two regions.

Osteoarthritis (OA) is an age-related degenerative disease that affects bones and joints. The hallmark pathogenesis of OA is associated with chondrocyte senescence. Surfactant protein D (SP-D) is a member of the innate immune proteins family, which can inhibit the immune inflammatory response of chondrocytes. However, the effect of SP-D on chondrocyte senescence phenotype is poorly studied. The present study investigated the phenotypic regulation of OA chondrocyte senescence mediated by SP-D and explored the underlying molecular mechanism.

In this study, an in vitro senescence chondrocyte model was generated by subjecting chondrocytes to IL-1β treatment. Furthermore, the expression of aging-related biomarkers and mitochondrial functions in SP-D overexpressing chondrocytes was observed. Co-immunoprecipitation was conducted to verify the association between SP-D and the identifed proteins within chondrocytes. Moreover, a rat OA model was established by destabilization of the medial meniscus surgery, and the effect of SP-D on reversing the aging phenotype of OA cartilage was investigated.

The results indicated that SP-D significantly decreased senescence and enhanced mitochondrial functions in senescent chondrocytes. The RNA-sequencing analysis revealed that the SIRT3/SOD2 pathway predominantly modulated the effect of SP-D on alleviating senescence. In addition, SP-D overexpression mitigated chondrocyte senescence, suppressed senescence-associated secretory phenotype (SASP) secretion and ameliorated mitochondrial damage. In the rat OA model, SP-D inhibited aging-related pathological changes by upregulating SIRT3/SOD2 pathway, thereby protecting the cartilage tissue integrity.

These findings indicate that SP-D modulates the inhibition of chondrocyte senescence by upregulating SIRT3/SOD2 pathway. These data indicate that targeting SP-D and the SIRT3/SOD2 pathway might be a promising therapeutic strategy for OA.

Osteoarthritis (OA) is a ubiquitous problem affecting dog joints, particularly the hip, elbow, stifle, and spine. OA most often results from developmental orthopedic problems such as hip dysplasia, elbow dysplasia, and patellar luxation and from injuries to the cranial cruciate ligament. Several management approaches have been proposed to manage OA, including steps to modulate growth, physical activity, and exercise, nutrition and nutritional supplementation, medications, physical rehabilitation, and surgical procedures. This article is the first in a series of articles that propose steps for practical OA management in dogs at various life stages. The review presented here focuses on growing dogs. The text describes the early pathophysiology and diagnosis of OA. The physical, nutritional, analgesic, and surgical management options of OA in growing dogs are presented. The application of these management options is described for three dogs. The overall approach to the management of OA in growing dogs is discussed.

Osteoarthritis (OA) is a common joint disease that poses a significant public health burden, particularly in older adults. Despite research on its impact, the role of bone mineral density (BMD) in OA prognosis remains underexplored. This study investigates the association between BMD, measured using dual-energy X-ray absorptiometry (DXA), and all-cause mortality in individuals with OA using data from the National Health and Nutrition Examination Survey (NHANES).

This retrospective cohort study utilized NHANES data from 1999 to 2018, including participants aged 20 years and older (n = 55,081). After excluding individuals with missing BMD or mortality data, 1,573 participants diagnosed with OA were analyzed.

The multivariate-adjusted hazard ratio (HR) for BMD and all-cause mortality was 0.344 (0.153, 0.774), indicating a protective effect of higher BMD. We observed an L-shaped relationship between BMD and mortality: a 1-unit decrease in BMD was associated with a 97.3% increased HR for mortality when BMD was below 1.216 g/cm² (HR 0.027, 95% CI 0.010-0.069). No significant association was found for higher BMD levels (HR 4.490, 95% CI 0.431-46.754). In age-stratified analysis, a significant association was found in both those under and over 50 years old.

This study reveals an L-shaped association between BMD and all-cause mortality in individuals aged 20 and older with OA, underscoring the importance of maintaining bone health in this population. These findings highlight BMD as a prognostic marker and suggest that monitoring BMD could improve clinical outcomes for OA patients.

Not applicable.

Troodontidae is a family of small-bodied theropods known predominantly from Asia but are comparatively scarce in North America. In the Dinosaur Park Formation (DPF) of Alberta, Canada, they are known predominantly from isolated material, precluding taxonomic and ontogenetic precision for this clade. Previously never sampled histologically within the DPF, here we attempt to fill in gaps in our knowledge about the life histories of the clade in this formation by histologically surveying metatarsals, which are among the most abundant and identifiable troodontid elements in the DPF. We sampled 11 metatarsals (three metatarsal IIs, three metatarsal IIIs and five metatarsal IVs) of varying sizes and included three pathological individuals to describe the microanatomy of both healthy and pathological metatarsals, determine the ontogenetic status of each element and graph their pattern of growth. Osteohistology reveals that troodontid metatarsals grew and remodelled asymmetrically within the cortex, ceasing growth and remodelling primarily along articular surfaces and entheses. Pathological individuals ranged from displaying features of response to localised stress (chronic callus formation and avulsion/chip fracture) to extreme modification in response to trauma and inflammation at the distal joint. Only the latter appeared to be related to overall growth, suggesting the condition either developed early and stunted growth or another underlying cause was responsible for both the stunted growth and the resulting pathological features observed. Overall, tracking the growth of the specimens reveals that there are at least two growth trajectories within the DPF differentiated by the timing of major growth spurts and growth plateaus. Whether this represents sexual dimorphism, taxonomic diversity, or another form of variation warrants further investigation.

This review summarises the role of Gli1+ (Glioma-associated oncogene homologue 1) mesenchymal stem cells in craniofacial growth and development or tissue repair, and their application in the treatment of some diseases.

The search for this narrative review was conducted in PubMed and Web of Science using relevant keywords, including checking reference lists of journal articles by hand searching.

Gli1+ mesenchymal stem cells play an important role in the growth and development of the skull, tooth, periodontium and mandibular condyle. They can be applied to the treatment of pulp and periodontal diseases, temporomandibular joint osteoarthritis and other diseases.

Gli1+ mesenchymal stem cells are crucial for the development and repair of craniofacial tissue.

Sulcus-deepening trochleoplasty is a well-established treatment option for patients presenting with severe trochlear dysplasia and patellar instability. However, concerns remain regarding its influence on cartilage integrity in the patellofemoral (PF) joint.

To assess the midterm effect of trochleoplasty on PF cartilage integrity in patients with severe trochlear dysplasia treated for patellar instability.

Cohort study; Level of evidence, 3.

A total of 75 patients with high-grade trochlear dysplasia (Dejour types B and C) who underwent patellar stabilizing surgery for patellar instability at a single institution were included. Of these, 42 patients underwent patellar stabilizing surgery without trochleoplasty (group I), while 33 patients underwent thin-flap sulcus-deepening trochleoplasty as part of their surgical treatment (group II). Preoperative and postoperative magnetic resonance imaging scans were retrospectively assessed to evaluate PF cartilage, grading from 0 (intact) to 4 (full-thickness lesion) for the medial, central, and lateral patella as well as the medial, central, and lateral trochlea. Associations between patient-specific characteristics, anatomic parameters, and chondral integrity were also assessed.

Patients underwent patellar stabilizing surgery at a mean age of 23.2 ± 8.0 years with a body mass index of 25.5 ± 5.0 kg/m2. Postoperative magnetic resonance imaging was performed at a mean of 35.2 ± 26.3 months (range, 6-118 months). Patients in group II were slightly older (25.0 ± 7.5 vs 21.8 ± 8.2 years, respectively; P = .032) and had a significantly higher preoperative tibial tubercle-trochlear groove distance (18.4 ± 4.0 vs 14.1 ± 3.4 mm, respectively; P < .001) and patellar tilt (26.4° ± 12.5° vs 13.2° ± 6.7°, respectively; P < .001) compared with patients in group I. Both groups showed similar preoperative cartilage integrity in the PF joint (not significant). Postoperatively, both groups had similar patellar chondral damage (not significant), but group II showed significantly greater trochlear chondral damage (P = .001 for medial; P < .001 for central; and P = .002 for lateral). In comparison to preoperatively, 92.9% to 97.6% of patients in group I had intact trochlear cartilage or an unchanged status of trochlear cartilage postoperatively compared with 36.4%to 63.6% of patients in group II; the incidence varied depending on the location (P = .001 for medial; P < .001 for central; and P = .008 for lateral). Among all PF parameters, only the postoperative sagittal tibial tubercle-trochlear groove distance was associated with the progression or new occurrence of chondral damage in the medial trochlea (r = 0.232; P = .045).

The integrity of the PF chondral layer remained unchanged in most patients treated for patellar instability in the setting of trochlear dysplasia. Yet, significantly more patients who underwent trochleoplasty showed a decline in trochlear chondral status at short-term to midterm follow-up.

Facet joint osteoarthritis (OA) is prevalent in patients with adolescent idiopathic scoliosis (AIS). The most pronounced OA presents above and below the curve's apex where the intervertebral rotation is the greatest. This indicates that facet joint OA is implicated and potentially contributes to AIS progression. OA impacts both cartilage and bone and we have previously demonstrated an association between lower bone quality and more severe OA in AIS facet joints. This study aimed to further investigate the molecular mechanisms underlying cartilage-bone crosstalk in the facet joints of patients with AIS.

Unbiased deep RNA sequencing was performed to compare gene expression in facet joint chondrocytes of age-matched AIS patients and non-scoliotic individuals. Differentially expressed genes of interest were validated through qPCR and ELISA in a larger sample cohort. Key regulatory pathways involved in cartilage-bone crosstalk were identified through bioinformatic analysis. Functional studies were conducted by treating chondrocytes with TLR2 and TLR4 agonists, collecting conditioned media, and administering it to an in vitro osteoclastogenesis model. The expression of M-CSF, a key regulatory factor influencing osteoclast proliferation, was measured in individual facet joint cartilage samples at different spinal levels and correlated with cartilage morphological grade and 3D structural parameters extracted from spine reconstruction.

One thousand four hundred twenty six upregulated genes were detected, and gene ontology analysis revealed a significant enrichment of the TLR pathway, and bone-regulating biological processes in AIS chondrocytes. TLR activation of AIS chondrocytes induced expression of bone-regulating factors, including M-CSF, a key regulator of osteoclast proliferation. Furthermore, secreted factors from AIS chondrocytes enhanced osteoclast proliferation and maturation, with a stronger effect observed following TLR pre-activation. Clinically, M-CSF expression was found to correlate strongly with increased OA severity and a greater degree of intervertebral axial rotation.

Together, our findings suggest that the TLR-M-CSF axis is implicated in osteoclastogenesis, resulting in increased bone turnover and may contribute to curve progression in AIS patients.

Uncoupled bone remodeling in the subchondral bone (SB) has recently been considered as an important process in the progression of knee osteoarthritis (KOA). In this study, we aimed to investigate changes in SB and articular cartilage using a mouse model of destabilization of the medial meniscus (DMM) and determine the effects of bone metabolism on KOA progression.

DMM or sham surgery was performed on the left knees of 40-week-old male wild-type (WT) mice and Tsukuba hypertensive mice (THM), which exhibit high-turnover bone metabolism. Bone volume/tissue volume (BV/TV) and bone mineral density (BMD) in the medial tibial SB were measured longitudinally in vivo using μCT at 0 (immediately after surgery), 1, 2, 4, 8, and 12 weeks postoperatively. Concurrently, histological evaluations of the articular cartilage in the medial tibial plateau were conducted. Furthermore, the number of endo-periosteal tartrate-resistant acid phosphatase-positive osteoclasts, trabecular RANKL-positive osteocytes, and osteocytes in the trabeculae were measured at 0, 1, 2, and 4 weeks.

In the WT + DMM group, BV/TV and BMD in the SB significantly decreased with time, whereas cartilage degeneration significantly increased. In the THM + DMM group, these changes in BMD and cartilage degeneration were significantly pronounced. Interestingly, in the THM + DMM group, BV/TV significantly decreased up to 4 weeks but then began to increase, although BMD continued to decrease until the 12-week mark. The number of osteoclasts and the percentage of RANKL-positive osteocytes per total number of osteocytes within the total trabecular bone area (%) in the WT + DMM group significantly increased with time, with a significant difference between the WT + DMM and WT + sham groups at 4 weeks. The number of osteocytes in the WT + DMM group significantly decreased with time, and the difference between the WT + DMM and WT + sham groups was significant at 4 weeks postoperatively. These histological changes were significantly enhanced in the THM + DMM group.

The results indicate that early-stage osteocyte death in the SB and RANKL-mediated osteoclastic SB loss precede histological cartilage degeneration and contribute to uncoupled bone remodeling at the later stage. Acceleration of disease processes in the THM + DMM group suggests that high-turnover bone metabolism is a potential risk factor for KOA. Maintaining SB integrity and avoiding continuous SB overload may be key strategies for mitigating disease progression.

Osteoarthritis (OA) is a prevalent chronic degenerative joint disorder characterized by cartilage degeneration, joint inflammation, and pain. The pathogenesis of OA still remains unclear. Among the various factors contributing to OA, the role of extracellular matrix (ECM) proteins, particularly thrombospondins (TSPs), has garnered significant attention. TSPs, a family of multifunctional extracellular matrix glycoproteins, are known to participate in numerous physiological and pathological processes, including cell adhesion, migration, differentiation, angiogenesis, and synaptogenesis through cell-cell and cell-matrix interactions. In this review, we provide a summary of the current understanding of TSP proteins in the pathogenesis of OA, including their effects on cartilage homeostasis, synovial inflammation, and subchondral bone remodeling and arthritic pain. We also review the evidence supporting the potential of TSP proteins as diagnostic biomarkers and therapeutic targets, with a focus on recent advances in cartilage regeneration, gene delivery therapy and pain management. Considering the multifaceted roles of TSP proteins in maintaining articular homeostasis, TSP proteins emerge as promising therapeutic targets for OA.

ACL injuries commonly lead to post-traumatic osteoarthritis (PTOA), but the underlying mechanism is not well-understood. One theorized mechanism is pathological bone remodelling following an ACL tear, for which high-resolution peripheral quantitative computed tomography (HR-pQCT) is uniquely positioned to investigate in vivo in humans. In this study, we longitudinally investigate the one-year changes in periarticular bone density and microarchitecture in the human knee following an ACL tear and reconstructive surgery using data sampled from an on-going observational cohort study. We reduce the number of individual microarchitectural parameters using factor analysis and model one-year changes with mixed-effects models, adjusting for the effects of age, sex, meniscus status, and the baseline microarchitectural state. We find significant evidence of persistent bone density losses one year after both injury and surgery. We also observe significant increases in trabecular separation post-injury, indicating significant structural degradation, and significant increases in subchondral bone plate density post-surgery, a sign of early stiffening. Finally, we observe minimal significant contrasts for the effects of age, sex, and meniscus status, while we observe that the state of the microarchitecture at baseline has significant and varied effects on the subsequent changes, suggesting that the influence of PTOA risk factors on post-injury and post-surgery bone changes may be mediated through the state of the periarticular microarchitecture at injury and/or at surgery. In summary, we found that degradation of periarticular bone microarchitecture was observed post-injury, densification of the subchondral bone plate was observed post-surgery, and the state of the bone microarchitecture at baseline may mediate the influence of PTOA risk factors on post-injury microarchitectural adaptations.

To investigate the role of osteoclast-derived apoptotic bodies (OC-ABs) in osteoarthritis (OA), specifically their impact on subchondral bone remodeling and disease progression, and to explore potential therapeutic strategies targeting OC-AB-induced pathways.

We utilized a mouse model of anterior cruciate ligament transection (ACLT) to simulate post-traumatic osteoarthritis (PTOA). Levels of OC-ABs were assessed in subchondral bone and correlated with OA severity. Additionally, apoptotic body-deficient MRL/lpr mice were analyzed to evaluate the direct contribution of OC-ABs to OA progression and subchondral bone remodeling. The involvement of OC-ABs in osteogenesis was further examined using mesenchymal stem cells (MSCs), with a focus on the RANKL reverse signaling pathway. The therapeutic potential of rapamycin to counteract OC-AB effects was tested.

Increased OC-AB accumulation in subchondral bone was positively correlated with OA severity in ACLT-induced mice. Apoptotic body-deficient MRL/lpr mice demonstrated slower OA progression and maintained more stable subchondral bone architecture, indicating a pathogenic role of OC-ABs in OA. OC-ABs significantly stimulated osteogenesis in MSCs via the RANKL reverse signaling pathway. Treatment with rapamycin effectively reversed OC-AB-induced subchondral bone formation, mitigated OA progression, and inhibited the RANKL reverse signaling pathway.

OC-ABs play a critical role in exacerbating OA by promoting subchondral bone remodeling via the RANKL reverse signaling pathway. Rapamycin presents as a promising therapeutic agent capable of mitigating OC-AB-driven pathology, highlighting new avenues for targeted OA treatment.

Despite osteoarthritis (OA) being recognised for over a century as a debilitating disease that affects millions, there are huge gaps in our understanding of the underlying pathophysiology that drives this disease. Present day studies that focussed on ubiquitination (Ub) and ubiquitylation-like (Ubl) modification related mechanisms have brought light into the possibility of attenuating OA development by targeting these specific proteins in chondrocytes. In the present review, we discuss recent advances in studies involving Ub ligases and deubiquitinating enzymes (DUBs) which are of importance in the development of OA, and may offer potential therapeutic strategies for OA. Such targets may involve attenuating proteases such as matrix metalloproteinases (MMP) 1, 8, 13, 4 and several A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) that are well known for their roles in cartilage breakdown. Ligases such as ubiquitin-conjugating enzymes (E2) and ubiquitin-ligating enzymes (E3) that are involved in extracellular matrix (ECM) degradation in OA and of their pathogenesis would be discussed. In addition to catabolic and degenerative downstream effects of Ub and DUBs in OA, inflammatory mechanisms most notably involving nuclear factor-kappa B (NF-κB) signalling pathways regulated through Ub and using various targeting molecules would also be highlighted. Challenges, gaps and insights from clinical trials will provide valuable guidance for future investigations on targeting ubiquitin-proteosome system (UPS) as a therapeutic option for OA.

Osteoarthritis (OA) is a progressive osteoarticular disease affecting the whole joint. In the United Kingdom, OA is the most prevalent joint disease, with knee osteoarthritis (KOA) being the most common type of OA. Key symptoms of KOA include knee pain, stiffness, and loss of physical function. Different types of exercise can be performed in people with KOA, which exert different magnitudes of impact forces on the knee joint, whereby the National Institute for Health and Care Excellence (NICE) OA guidelines in fact recommend exercise as the core form of therapeutic OA management. However, the optimal type or dose - the cumulative intensity, duration, and frequency - of therapeutic exercise that most effectively provides KOA management is not currently known. This review aims to summarise and compare the literature, discussing optimal exercise modalities and doses for the management of KOA. All exercise modalities proved similarly beneficial at managing KOA with comparable improvements to knee pain, stiffness, and physical function, therefore with no optimal exercise modality identified. Benefits to KOA management was observed in everyone, including the elderly, obese, and those with severe KOA. Although, in those with severe KOA, walking was observed to only prevent further deterioration, rather than induce any symptomatic improvement. Furthermore, there was minimal difference between exercise modalities in relation to the improvements not only in KOA symptoms, but also modifiable KOA risk factors, adherence, adverse events, and QoL. Assessment of the dose-response relationship of each exercise modality showed that any dose of regular exercise was effective. Although, moderate intensity exercise performed three times weekly for 20-to-60-min appears optimal for KOA symptom control following most exercise modalities. Therefore, those with KOA should be encouraged to continue whatever exercise they currently do as should effectively manage symptoms, regardless of the modality or dose. However, those who do no exercise should use the present review in collaboration with clinicians via shared decision making to create a holistic exercise prescription. In summary, this review contributes to the literature through comprehensive discussion of different exercise modalities and doses in managing not only KOA symptoms, but modifiable KOA risk factors, exercise adherence, adverse events, and QoL. Additionally, summarised findings are discussed to give practical exercise recommendations to promote effective KOA management and recommendations for ongoing research.

Arthritis is an inflammatory joint disorder that progressively impairs function and diminishes quality of life. Conventional therapies often prove ineffective, as oral administration lacks specificity, resulting in off-target side effects like hepatotoxicity and GIT-related issues. Intravenous administration causes systemic side effects. The characteristic joint-localized symptoms such as pain, stiffness, and inflammation make the localized drug delivery suitable for managing arthritis. Topical/transdermal/intra-articular routes have become viable options for drug delivery in treating arthritis. However, challenges with those localized drug delivery routes include skin barrier and cartilage impermeability. Additionally, conventional intra-articular drug delivery also leads to rapid clearance of drugs from the synovial joint tissue. To circumvent these limitations, researchers have developed nanocarriers that enhance drug permeability through skin and cartilage, influencing localized action. Gel-based nanoengineered therapy employs a gel matrix to incorporate the drug-encapsulated nanocarriers. This approach combines the benefits of gels and nanocarriers to enhance therapeutic effects and improve patient compliance. This review emphasizes deep insights into drug delivery using diverse gel-based novel nanocarriers, exploring their various applications embedded in hyaluronic acid (biopolymer)-based gels, carbopol-based gels, and others. Furthermore, this review discusses the influence of nanocarrier pharmacokinetics on the localization and therapeutic manipulation of macrophages mediated by nanocarriers. The ELVIS (extravasation through leaky vasculature and inflammatory cell-mediated sequestration) effect associated with arthritis is advantageous in drug delivery. Simply put, the ELVIS effect refers to the extravasation of nanocarriers through leaky vasculatures, which finally results in the accumulation of nanocarriers in the joint cavity.

Subchondral milieu has been the region of interest in recent clinical trials demonstrating it as an effective treatment focus in knee osteoarthritis (OA). However, a systematic analysis of the subchondral cell population density is lacking in knee OA. Hence, this study aims to analyze the cell population density of the subchondral zone for every stage of cartilage degeneration to analyze the rationale behind this evolving treatment method for knee OA.

This is an ex vivo histopathological analysis of the distal femur and proximal tibia articular specimens from the patients undergoing total knee replacement for primary knee OA between November 2023 and March 2024. Two pathologists independently graded and analyzed the subchondral cell density based on the International Cartilage Repair Society cartilage injury grading system.

We noted a significant association between the grade of cartilage degeneration and the subchondral cell density (r = 0.831, P < 0.001). We noted a statistically significant decrease in the cell density for every stage of cartilage injury compared to the control (P < 0.001). We also noted a significant decrease in cell density between the early and late stages of cartilage degeneration (P < 0.001). We did not note any significant difference in the cell density between the tibial and femoral articular cartilage for every grade of cartilage degeneration analyzed (P = 0.432).

Subchondral cell density decreases significantly with increasing grade of degeneration in knee OA. Subchondral milieu warrants attention to be considered as a potential treatment focus that could alter the disease progression in knee OA.

The role of extracellular vesicles (EVs) derived from inflammatory chondrocytes in EV-based therapy for osteoarthritis (OA) has received little attention. We examined the effects of EVs derived from both normal rat chondrocytes (nEVs) and IL-1β-treated rat chondrocytes (iEVs) on IL-1β-treated rat chondrocytes, macrophages, and osteoblasts, alongside mRNA-seq and miRNA-seq analyses of both them. Additionally, nEVs and iEVs were administered intra-articularly in the joints of rat models subjected to anterior cruciate ligament transection (ACLT), and the morphological alterations across the joints were assessed. These findings indicated that iEVs, compared with nEVs, significantly enhanced collagen II synthesis in IL-1β-treated chondrocytes, accompanied by marked increases in ER stress and autophagy. In comparison to nEVs, iEVs exhibited a greater effect on facilitating M2-type macrophage polarization while simultaneously diminishing M1-type polarization, a process likely mediated by the downregulation of chemotactic cytokines such as Cxcl10, Ccl5, Cxcl9, Cxcl1, and Cxcl11. iEVs exerted a more pronounced influence on the phenotypic characteristics of IL-1β-treated osteoblasts than nEVs. In the ACLT-rat model, iEVs, akin to nEVs, effectively mitigated articular cartilage degradation. However, there was no significant difference in OARSI Scores between the two groups, despite iEVs exerting a greater effect on increasing hyaline cartilage thickness and proteoglycan content. iEVs were superior to nEVs in attenuating synovium inflammation and promoting trabecula formation in the femur subchondral bone. Consequently, iEVs, akin to nEVs, significantly alleviated OA-induced damage. Moreover, iEVs outperformed nEVs in certain aspects, notably in augmenting hyaline cartilage, reducing synovium inflammation, and promoting trabecular formation in the subchondral bone during the early stage of OA.

Osteoarthritis (OA) is heterogeneous and involves structural changes in the whole joint, such as cartilage, meniscus/labrum, ligaments, and tendons, mainly with short T2 relaxation times. Detecting OA before the onset of irreversible changes is crucial for early proactive management and limit growing disease burden. The more recent advanced quantitative imaging techniques and deep learning (DL) algorithms in musculoskeletal imaging have shown great potential for visualizing "pre-OA." In this review, we first focus on ultrashort echo time-based magnetic resonance imaging (MRI) techniques for direct visualization as well as quantitative morphological and compositional assessment of both short- and long-T2 musculoskeletal tissues, and second explore how DL revolutionize the way of MRI analysis (eg, automatic tissue segmentation and extraction of quantitative image biomarkers) and the classification, prediction, and management of OA. PLAIN LANGUAGE SUMMARY: Detecting osteoarthritis (OA) before the onset of irreversible changes is crucial for early proactive management. OA is heterogeneous and involves structural changes in the whole joint, such as cartilage, meniscus/labrum, ligaments, and tendons, mainly with short T2 relaxation times. Ultrashort echo time-based magnetic resonance imaging (MRI), in particular, enables direct visualization and quantitative compositional assessment of short-T2 tissues. Deep learning is revolutionizing the way of MRI analysis (eg, automatic tissue segmentation and extraction of quantitative image biomarkers) and the detection, classification, and prediction of disease. They together have made further advances toward identification of imaging biomarkers/features for pre-OA. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

This study aims to investigate the mechanism underlying the effect of Duhuo Jisheng Decoction on the repair of rabbit articular cartilage injury through a reduction in the inflammatory response mediated by the Transforming growth factor (TGF)-β/Smad signaling pathway.

A rabbit articular cartilage injury model was constructed using a ring bone extraction drill. Twenty-four Japanese white rabbits were randomly divided into six groups, namely Sham operation, model, low-dose Duhuo Jisheng Decoction, medium-dose Duhuo Jisheng Decoction, high-dose Duhuo Jisheng Decoction, and positive control groups. The treatment lasted 12 weeks. Gross observation, International Cartilage Repair Society score, Wakitani score, and Micro-computed tomography analysis were used to evaluate the structural repair of cartilage injury. Histology and immunohistochemistry were used to observe the proteoglycan, P-TβRII, P-Smad2, and type II collagen expression levels. Enzyme-linked immunosorbent assay was used to analyze the concentrations of Matrix Metalloproteinase-13 and Syndecan-4 in the joint fluid; and RT-PCR and Western Blot were used to observe the mRNA and protein expressions of ALK5, Sox-9, P-Smad3, and TGF-β1 at the injury repair site.

The repair effect of cartilage injury, as seen through gross observation and quantitative scoring, was better in all the Duhuo Jisheng Decoction treatment groups than in the model group. The medium dose group of Duhuo Jisheng Decoction had the best repair effect. We observed remarkable structural restoration of cartilage injury in the medium-dose Duhuo Jisheng Decoction group, with the subchondral bone presenting a distinct hierarchy, and parameters such as bone volume fraction and trabecular separation/spacing being significantly augmented. We found high expression levels of proteoglycans, P-TβRII, P-Smad2, and type II collagen. The concentrations of Matrix Metalloproteinase-13 and Syndecan-4 in the joint fluid were significantly lower following treatment. The low gene expression levels of ALK5, Sox-9, P-Smad3, and TGF-β1 in the injury site of the model group could be reversed in the medium-dose Duhuo Jisheng Decoction group.

Duhuo Jisheng Decoction can repair rabbit cartilage injury and reverse the levels of inflammatory factors in the joint fluid. The mechanism underlying its therapeutic effect is related to the activation of the TGF-β/Smad signaling pathway. This study provides a reliable basis for using Duhuo Jisheng Decoction to treat cartilage injury following knee osteoarthritis.

Osteoarthritis (OA) is a common chronic musculoskeletal disease with heterogeneous clinical manifestations and variable responses to different treatments. Unfortunately, there is no effective disease modifying therapy at present that can alter the natural course of the disease. Cell therapy based on mesenchymal stromal cells (MSCs) may offer an attractive therapeutic option for OA with their multiple modes of action, particularly immune-regulatory and regenerative capacities.

In this narrative review, updates on mode of action based on patient's data, factors that can influence the efficacy of MSC treatment, current status in clinical application of MSCs as seen from randomized, controlled OA trials are introduced as well as the author's perspectives in the future of MSCs as OA therapeutics.

Symptomatic relief is not sufficient to justify the high cost associated with culture-expanded stem cells. Its advantages and efficacy over simple and low risk/cost modalities should be seriously reevaluated. Also, as the short-term strategy, efforts should be made to lower the cost of MSC therapy. In the future, multiomics technology may help to predict that subgroup of patients who will favorably respond to stem cell treatment, which would enhance the cost effectiveness and therapeutic benefit of MSC therapy.

Isoliensinine is an active compound derived from Nelumbo nucifera which has long been used for its anti-inflammatory properties. However, the mechanism of Isoliensinine in the treatment of osteoarthritis is poorly known.

The present study aims to investigate whether Isoliensinine could alleviate osteoarthritis by regulating MAPK/NF-κB signaling pathway-mediated pyroptosis.

Network pharmacology and KEGG enrichment analysis were used to identify the therapeutic targets of Isoliensinine for OA. Molecular docking was used to confirm the binding ability of Isoliensinine and related proteins. In vitro, chondrocytes were stimulated with IL-1β to construct an inflammatory model and treated with Isoliensinine. The viability of the cells was assessed using the CCK-8 kit. The apoptosis rate of cells was measured using Annexin V-FITC/PI assay. And assessed the levels of ROS, lipid-ROS, and mitochondrial membrane potential. Corresponding assay kits were utilized to measure the levels of MDA and SOD. Subsequently, the anabolic and catabolic markers in chondrocytes, alongside inflammatory targets were measured by RT-PCR and Western blot. The expression level of pyroptosis and MAPK/NF-κB signaling pathway-related targets was examined. Furthermore, we constructed a rat osteoarthritis model using ACLT surgery. We then assessed the progression of osteoarthritis by Micro-CT, H&E staining, S&F staining and immunohistochemistry.

Enrichment analysis showed that Isoliensinine treatment of osteoarthritis may be through the MAPK/NF-κB pathway, and molecular docking showed that Isoliensinine and MAPK/NF-κB pathway proteins had a good binding ability. Data showed that Isoliensinine could reduce ECM degradation and inflammation, and inhibit IL-1β-induced apoptosis. It also mitigated ROS and LPO activation, regulated mitochondrial dysfunction, and reduced intracellular oxidative stress levels. Furthermore, Western blot showed that Isoliensinine also inhibited the activation of the MAPK/NF-κB pathway, thereby inhibiting the pyroptosis of chondrocytes. In vivo, Micro-CT, H&E staining and S&F staining results showed that Isoliensinine could effectively improve joint damage caused by osteoarthritis. And IHC analyses indicated NLRP3, MMP3 protein expression were significantly diminished and Collagen II expression was increased in the Isoliensinine treatment groups.

In conclusion, our study suggested that Isoliensinine mitigates ECM degradation, oxidative stress, chondrocytes apoptosis, and pyroptosis through the inhibition of the MAPK and NF-κB pathways, thereby delaying the progression of osteoarthritis.

This study aimed to investigate the relationship between clinical findings and the trabecular microstructure of the subchondral bone in patients with hip osteoarthritis (OA) due to developmental dysplasia of the hip (DDH) using multidetector row computed tomography (MDCT).

A total of 63 patients (69 hips) with OA due to DDH were retrospectively reviewed, with 12 healthy controls being included for comparison. Clinical evaluation was performed using the Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ). The trabecular bone microstructure was analyzed using MDCT. Regions of interest in the subchondral trabecular bones of the acetabulum and femoral head were defined in the coronal view, and various trabecular microstructural parameters were evaluated.

Bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) exhibited a significant positive correlation with the OA stage, whereas trabecular separation (Tb.Sp) showed a negative correlation. In addition, BV/TV and Tb.Th were negatively correlated with the JHEQ total and pain scores, whereas Tb.Sp was positively correlated with the pain score in all regions.

This is the first study to evaluate the bone microstructure and its relationship with clinical findings in patients with hip OA due to DDH. Our findings suggest that as OA progresses, osteosclerotic changes increase in the acetabulum and femoral head; these changes are associated with worsening clinical symptoms, particularly pain. Targeting the subchondral bone may emerge as a novel treatment strategy for patients with OA due to DDH; nevertheless, further comprehensive studies are required.

Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation. We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.

Background The calcified cartilage layer and subchondral bone plate (SBP) contribute to osteoarthritis development. Three-dimensional (3D) ultrashort echo-time (UTE) MRI can help to evaluate calcified cartilage and SBP in various stages of cartilage degradation. Purpose To compare calcified cartilage and SBP abnormalities using 3D UTE MRI with cartilage degradation and osteochondral junction (OCJ) abnormalities observed at proton-density fast spin-echo with fat suppression (PDFS) MRI. Materials and Methods Between April 2018 and March 2019, 143 participants were prospectively enrolled in this study and underwent routine knee MRI with an additional sagittal 3D UTE MRI examination for chronic knee pain. The MRI scans were retrospectively analyzed by two musculoskeletal radiologists independently and at consensus. Cartilage degradation grades and OCJ abnormalities were evaluated at PDFS MRI. Calcified cartilage and SBP abnormalities were assessed at 3D UTE MRI by considering the location of cartilage degradation. The relationship between cartilage degradation grade and abnormalities of calcified cartilage and SBP was assessed using Spearman rank correlation analysis. The association between OCJ abnormalities on PDFS MRI scans and calcified cartilage and SBP abnormalities was analyzed using logistic regression models. Results In total, 143 knees (71 right and 72 left knees) from 143 participants (mean age, 50.8 years ± 17.6 [SD]; 72 male and 71 female participants) were analyzed. On 3D UTE MRI scans, calcified cartilage defects showed a moderate positive correlation with the cartilage degradation grade (ρ = 0.49-0.52; P < .001). Calcified cartilage thinning (ρ = 0.2-0.3; P < .001), SBP irregular thickening (ρ = 0.3-0.35; P < .001), and defects (ρ = 0.34-0.42; P < .001) exhibited a weak positive correlation with the cartilage degradation grade. OCJ abnormalities depicted at PDFS MRI were associated with calcified cartilage and SBP abnormalities (P < .05). Conclusion Calcified cartilage layer and SBP abnormalities at 3D UTE MRI were associated with cartilage degradation and OCJ abnormalities depicted at PDFS MRI. © RSNA, 2024 Supplemental material is available for this article.

Osteoarthritis (OA) is characterised by the failure of normal biological processes to repair following damage. Traditionally, OA was considered a "wear and tear" disorder; however, it is now a recognised inflammatory condition, preceded by molecular modifications. The aim of this study was to evaluate inflammatory markers among individuals with early knee OA (eKOA) and well-matched asymptomatic controls.

Twenty six eKOA (females, n = 13; age = 60.2 ± 5.4 yrs, height = 1.73 ± 0.11 m, body mass = 77.8 ± 12.8 kg, body fat = 33.9 ± 8.5%) and twenty-three asymptomatic individuals (females, n = 14; age = 59.9 ± 5.5yrs, height = 1.71 ± 0.09 m, body mass = 72.6 ± 11.3 kg, body fat = 30.4 ± 8.2%) were recruited. The Timed Up and Go, and the 6 Minute Walk Tests evaluated physical function in addition to pain specific questionnaires (KOOS and ICOAP). Serum levels of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8(CXCL8), IL-10, hsCRP and TNF-α were quantified using a multiplex assay via V-plex®Sector Imager 2400.

As hypothesised, only KOOS and EQ-5D-5L metrics differed between the groups for non-blood derived measures (p < 0.04). Only IL-6 was higher in eKOA (P = 0.02; 95% CI = 0.202; by 0.197 pg/mL; 34.5%). Among eKOA, IL-6 did not relate to severity of KOOS pain (P = 0.696, r = -0.088), but had a positive relationship with ICOAP consistent (r = 0.469, P = 0.045) rather than intermittent pain. There was a moderate correlation between 6MWD and IL-8 (r = 0.471, P = 0.012).

Our results illustrate the potential for IL-6 as a biomarker for eKOA, and introduce the proposition for particular consideration in those with consistent pain. Further, for the first time the present data showed greater walking distance in eKOA with lower circulating IL-8. Future work should seek to verify these results and further investigate IL-6 and IL-8 related molecular pathways in eKOA, and their potential relationships with consistent knee pain and physical function.

Subchondral bone sclerosis is a key characteristic of osteoarthritis (OA). Prior research has shown that Forkhead box C1 (FoxC1) plays a role in the synovial inflammation of OA, but its specific role in the subchondral bone of OA has not been explored. Our research revealed elevated expression levels of FoxC1 and Piezo1 in OA subchondral bone tissues. Further experiments on OA subchondral bone osteoblasts with FoxC1 or Piezo1 overexpression showed increased cell proliferation activity, expression of Yes-associated Protein 1 (YAP) and osteogenic markers, and secretion of proinflammatory factors. Mechanistically, the overexpression of FoxC1 through Piezo1 activation, in combination with downstream YAP signaling, led to increased levels of alkaline phosphatase (ALP), collagen type 1 (COL1) A1, RUNX2, Osteocalcin, matrix metalloproteinase (MMP) 3, and MMP9 expression. Notably, inhibition of Piezo1 reversed the regulatory function of FoxC1. The binding of FoxC1 to the targeted area (ATATTTATTTA, residues +612 to +622) and the activation of Piezo1 transcription were verified by the dual luciferase assays. Additionally, Reduced subchondral osteosclerosis and microangiogenesis were observed in knee joints from FoxC1-conditional knockout (CKO) and Piezo1-CKO mice, indicating reduced lesions. Collectively, our study reveals the significant involvement of FoxC1 in the pathologic process of OA subchondral bone via the Piezo1/YAP signaling pathway, potentially establishing a novel therapeutic target.

The aberrant H-type vessel formation was found to be intimately linked to subchondral bone remodeling during osteoarthritis (OA) development. Herein, we investigated the role and mechanism of osteoblast-secreted slit guidance ligand 3 (Slit3) in H-type vessel formation during OA progression.

Slit3 protein levels in subchondral bone samples of OA patients were detected. The isolated osteoblasts were transfected with Slit3 overexpression or knockdown plasmids, and their conditioned medium was cultured with endothelial progenitor cells (EPCs). The migration, tube formation, VEGF, and H-type vessel marker protein CD31 and endomucin (EMCN) levels in EPCs were accessed. The interactions between Slit3 and roundabout (Robo) family members were validated by Co-IP assay. Besides, whether the Slit3/Robo signaling affects the transforming growth factor β1 (TGF-β1)/SMADs pathway was determined. Additionally, sh-Slit3 was injected into OA mice, followed by the detection of articular cartilage degradation, subchondral bone remodeling, and H-type vessel formation.

Slit3 was upregulated in subchondral bone tissues of OA patients. Slit3 overexpression in osteoblasts intensified the migration and H-type vessel formation of EPCs, while Slit3 knockdown showed the opposite results. Slit3 overexpression enhanced Robo1 protein level. Robo1 knockdown abrogated Slit3-mediated migration and H-type vessel formation in EPCs. Slit3 activated the TGF-β1/SMADs pathway in EPCs, which might be associated with H-type vessel formation in EPCs. Additionally, Slit3 silencing restrained articular cartilage degradation, aberrant subchondral bone formation, and H-type vessel formation in OA mice.

Inhibition of Slit3/Robo1 signaling alleviates osteoarthritis in mice by reducing abnormal H-type vessel formation in the subchondral bone.

Knee osteoarthritis (KOA) is the most common type of joint disease in elderly people and is characterized by pain and dysfunction. Although the monoiodoacetate (MIA)-induced model is widely used as a rodent KOA model, it is important to acknowledge the inherent limitations of this model, as the MIA model develops complex pathological phases on a daily basis. An accurate understanding of this model and the selection of an appropriate time point according to the target for drug candidates can lead to the development of clinically effective drugs.

Changes in the pathological state of the MIA model were assessed via histopathological evaluation. Clodronate, a bisphosphonate, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), were selected as models of clinically effective drugs due to their different mechanisms of action. The analgesic effects of both drugs on the MIA model were evaluated. The long-term effect of clodronate on subchondral bone osteoclasts was also evaluated.

Histopathological evaluation revealed that MIA-induced symptomatic behavior occurred in the early and late phases and was accompanied by synovial inflammation and osteoclast-related joint degeneration, respectively. Although clodronate inhibited symptomatic behavior and prevented cartilage degeneration from the early to late phases, diclofenac inhibited symptomatic behavior only in the early phase. Clodronate acted locally and inhibited the activation of subchondral osteoclasts.

Pathological changes, such as synovial changes in the early phase and knee joint degeneration in the late phase, in the MIA model are similar to those in human KOA. Our results indicate that the early phase in the MIA model is appropriate for evaluating the effects of anti-inflammatory agents such as NSAIDs and corticosteroids. The late phase in the MIA model is appropriate for evaluating the effects of drugs that act on cartilage and subchondral bone.

Background and Objectives: Knee osteoarthritis (KO) stands as the third leading cause of disability among the elderly, causing pain, reduced quality of life, and decreased functionality. The objective of this study is to assess the effects of an active neurodynamic technique programme at home on pain, quality of life, and function among individuals with KO. Materials and Methods: Thirty-five participants (69.7% women) aged ≥50 years with KO (Kellgren-Lawrence grades I-II) performed a femoral nerve mobilization programme at home for 6-8 weeks (20 repetitions per day). Pain intensity, using the numerical rating scale (NRS), pressure pain thresholds (PPTs), central sensitization inventory (CSI), temporal assessment, pain modulation, Knee Injury and Osteoarthritis Outcome Score (KOOS), and the 12-item Short Form Survey questionnaire (SF-12) were collected before, after the intervention, and at one, three, six, and twelve months. Results: Participants improved significantly in pain (p < 0.05), with the improvement maintained throughout the follow-up in the NRS and for at least one month in the PPT. There were also statistically significant (p < 0.05) improvements in all subscales of the KOOS, which were maintained throughout the follow-up. Improvements were also found in the CSI and CPM. Conclusions: A home-based active neurodynamic programme for the femoral nerve has been demonstrated to yield positive effects on pain and function in patients with KO.

Early diagnosis of post-traumatic osteoarthritis (PTOA) is critical for designing better treatments before the degradation becomes irreversible. We utilized multimodal high-resolution imaging to investigate early-stage deterioration in articular cartilage and the subchondral bone plate from a sub-critical impact to the knee joint, which initiates PTOA. The knee joints of 12 adult rabbits were mechanically impacted once on the femoral articular surface to initiate deterioration. At 2- and 14-week post-impact surgery, cartilage-bone blocks were harvested from the impact region in the animals (N = 6 each). These blocks were assessed for deterioration using polarized light microscopy (PLM), microcomputed tomography (μCT), and biochemical analysis. Statistically significant changes were noted in the impact tissues across the calcified zone (CZ) at 14 weeks post-impact: the optical retardation values in the CZ of impact cartilage had a drop of 29.0% at 14 weeks, while the calcium concentration in the CZ of impact cartilage also had a significant drop at 14 weeks. A significant reduction of 6.3% in bone mineral density (BMD) was noted in the subchondral bone plate of the impact samples at 14 weeks. At 2 weeks post-impact, only minor, non-significant changes were measured. Furthermore, the impact knees after 14 weeks had greater structural changes compared with the 2-week impact knees, indicating progressive degradation over time. The findings of this study facilitated a connection between mineralization alterations and the early deterioration of knee cartilage after a mechanical injury. In a broader context, these findings can be beneficial in improving clinical strategies to manage joint injuries.

Posttraumatic osteoarthritis (PTOA) commonly develops following anterior cruciate ligament (ACL) injuries, affecting around 50% of individuals within 10-20 years. Recent studies have highlighted early changes in subchondral bone structure after ACL injury in adolescent or young adult mice, which could contribute to the development of PTOA. However, ACL injuries do not only occur early in life. Middle-aged and older patients also experience ACL injuries and PTOA, but whether the aged subchondral bone also responds rapidly to injury is unknown. This study utilized a noninvasive, single overload mouse injury model to assess subchondral bone microarchitecture, turnover, and material properties in both young adults (5 months) and early old age (22 months) female C57BL/6JN mice at 7 days after injury. Mice underwent either joint injury (i.e., produces ACL tears) or sham injury procedures on both the loaded and contralateral limbs, allowing evaluation of the impacts of injury versus loading. The subchondral bone response to ACL injury is distinct for young adult and aged mice. While 5-month mice show subchondral bone loss and increased bone resorption postinjury, 22-month mice did not show loss of bone structure and had lower bone resorption. Subchondral bone plate modulus increased with age, but not with injury. Both ages of mice showed several bone measures were altered in the contralateral limb, demonstrating the systemic skeletal response to joint injury. These data motivate further investigation to discern how osteochondral tissues differently respond to injury in aging, such that diagnostics and treatments can be refined for these demographics.

This comprehensive review examines the relationship between osteoarthritis (OA) and osteoporosis (OP), two common disorders in the elderly. OA involves joint cartilage degeneration and pain, while OP leads to fractures due to reduced bone mass. Despite different pathologies, both conditions share risk factors such as age and genetics. Studies reveal mixed results: some show higher bone mineral density (BMD) in OA patients, suggesting an inverse relationship, while others find no significant link. Proposed mechanisms include mechanical loading, bone remodeling, and inflammation. Clinical strategies focus on maintaining bone health in OA and monitoring joint health in OP, with treatments like bisphosphonates and exercise. Understanding these interactions is crucial for developing integrated treatments to improve patient outcomes and quality of life. Further research is needed to clarify these complex mechanisms.

This randomized controlled trial (RCT) investigated whether adding daily use of flat flexible footwear (FFF) to a strengthening and aerobic exercise program improved short- and longer-term outcomes compared with adding stable supportive shoes (SSS) in people with medial tibiofemoral OA.

Participants (n = 97) with medial tibiofemoral OA were randomly assigned (1:1) to the FFF (n = 50) or SSS (n = 47) group. Participants in both groups received a 9-month intervention (3 months supervised followed by 6 months unsupervised exercise). The primary outcome was the change in knee pain on walking at 3 months measured using an 11-point numeric rating scale (NRS). Secondary outcomes included the change from baseline to 3 and 9 months in the severity of knee pain overall (NRS), physical function (WOMAC subscale), habitual physical activity level (Physical Activity Scale for the Elderly), quality of life (QoL) (European Quality of Life 5-Dimensions 5-Levels questionnaire) and markers of inflammation (effusion and Hoffa synovitis) and structural disease progression (bone marrow lesions).

There were no significant differences between the groups in the change in pain on walking [between-group difference -0.67 (95% CI -1.62, 0.29)] at 3 months. Knee pain on walking and overall knee pain significantly decreased in both groups at 3 and 9 months. Physical function and QoL improved in both groups at 3 and 9 months. We found no between-group differences in any secondary outcome at any time.

FFF added to exercise therapy did not provide additional better symptom nor structure-modification benefit compared with conventional SSS and exercise in people with medial tibiofemoral OA.

ClinicalTrials.gov (http://clinicaltrials.gov), NCT03796832.

Bisphosphonates (BP) are considered a treatment option for osteoarthritis (OA) due to reduction of OA-induced microtrauma in the bone marrow, stabilization of subchondral bone (SB) layer and pain reduction. The effects of high-dose alendronate (ALN) treatment on SB and articular cartilage after destabilization of the medial meniscus (DMM) or Sham surgery of male C57Bl/6J mice were analyzed. We performed serum analysis; histology and immunohistochemistry to assess the severity of OA and a possible pain symptomatology. Subsequently, the ratio of bone volume to total volume (BV/TV), epiphyseal trabecular morphology and the bone mineral density (BMD) was analyzed by nanoCT. Serum analysis revealed a reduction of ADAMTS5 level. The histological evaluation displayed no protective effect of ALN-treatment on cartilage erosion. NanoCT-analysis of the medial epiphysis revealed an increase of BV/TV in ALN-treated mice. Only the DMM group had significantly higher SB volume accompanied by decreased subchondral bone surface. Furthermore Nano-CT analysis revealed an increase in trabecular density and number, a decreased BMD and reduced osteophyte formation in the ALN mice. ALN treatment affected bone micro-architecture by reducing osteophytosis with simultaneous increasing subchondral bone plate thickness, trabecular thickness and BMD. Accordingly, ALN cannot be considered as a potential treatment strategy in general, however in a subgroup of patients with high bone turnover in an early-stage of OA, ALN might be an option when applied during a restricted time frame.

This study aimed to define the histopathology of degenerated humeral head cartilage and synovial inflammation of the glenohumeral joint in patients with omarthrosis (OmA) and cuff tear arthropathy (CTA). Additionally, the potential of immunohistochemical tissue biomarkers in reflecting the degeneration status of humeral head cartilage was evaluated.

Specimens of the humeral head and synovial tissue from 12 patients with OmA, seven patients with CTA, and four body donors were processed histologically for examination using different histopathological scores. Osteochondral sections were immunohistochemically stained for collagen type I, collagen type II, collagen neoepitope C1,2C, collagen type X, and osteocalcin, prior to semiquantitative analysis. Matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 levels were analyzed in synovial fluid using enzyme-linked immunosorbent assay (ELISA).

Cartilage degeneration of the humeral head was associated with the histological presentation of: 1) pannus overgrowing the cartilage surface; 2) pores in the subchondral bone plate; and 3) chondrocyte clusters in OmA patients. In contrast, hyperplasia of the synovial lining layer was revealed as a significant indicator of inflammatory processes predominantly in CTA. The abundancy of collagen I, collagen II, and the C1,2C neoepitope correlated significantly with the histopathological degeneration of humeral head cartilage. No evidence for differences in MMP levels between OmA and CTA patients was found.

This study provides a comprehensive histological characterization of humeral cartilage and synovial tissue within the glenohumeral joint, both in normal and diseased states. It highlights synovitis and pannus formation as histopathological hallmarks of OmA and CTA, indicating their roles as drivers of joint inflammation and cartilage degradation, and as targets for therapeutic strategies such as rotator cuff reconstruction and synovectomy.