Subchondral Bone Changes Research Articles

Development of a Microfluidic Vascularized Osteochondral Model as a Drug Testing Platform for Osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by changes in cartilage and subchondral bone. To date, there are no available drugs that can counteract the progression of OA, partly due to the inadequacy of current models to recapitulate the relevant cellular complexity. In this study, an osteochondral microfluidic model is developed using human primary cells to mimic an OA-like microenvironment and this study validates it as a drug testing platform. In the model, the cartilage compartment is created by embedding articular chondrocytes in fibrin hydrogel while the bone compartment is obtained by embedding osteoblasts, osteoclasts, endothelial cells, and mesenchymal stem cells in a fibrin hydrogel enriched with calcium phosphate nanoparticles. After developing and characterizing the model, Interleukin-1β is applied to induce OA-like conditions. Subsequently, the model potential is evaluated as a drug testing platform by assessing the effect of two anti-inflammatory drugs (Interleukin-1 Receptor antagonist and Celecoxib) on the regulation of inflammation- and matrix degradation-related markers. The model responded to inflammation and demonstrated differences in drug efficacy. Finally, it compares the behavior of the "Cartilage" and "Cartilage+Bone" models, emphasizing the necessity of incorporating both cartilage and bone compartments to capture the complex pathophysiology of OA.

Factors Influencing Long-term Outcomes After Matrix-Induced Autologous Chondrocyte Implantation: Long-term Results at 10 Years

Background: Matrix-induced autologous chondrocyte implantation (MACI), the third-generation of the technique, is an established procedure for the treatment of focal cartilage defects in the knee. However, the literature lacks long-term results of MACI with good statistical power. Purpose: To determine long-term survival and patient-reported outcomes (PROs) in a representative cohort and to identify patient- and surgery-related parameters that may influence long-term clinical outcomes. Study Design: Case series; Level of evidence, 4. Methods: A total of 103 patients were clinically evaluated at the current follow-up of 8.1 years (range, 5-11.9 years). PRO measures (PROMs) included the Knee injury and Osteoarthritis Outcome Score (KOOS), EQ-5D, visual analog scale for pain, and Tegner Activity Scale. Magnetic resonance imaging results were evaluated by using the AMADEUS (area measurement and depth and underlying structures) and MOCART (magnetic resonance observation of cartilage repair tissue) 2.0 knee score classification systems. Potential factors influencing PROs were first identified univariately and investigated in a multivariate regression model. Results: The defects had a mean size of 4.8 cm2 (range, 1.2-12 cm2) and were predominantly femorotibial (66%). The mean Kaplan-Meier survival rate of revision for any reason was 97.2% ± 1.6% at 10 years. In comparison to preoperative values, all PROMs were significantly improved at the current follow-up (P < .05). The MOCART 2.0 score peaked at 12 months (mean, 80.2 ± 15.3 months) and showed no significant change at 96 months (mean, 76.1 ± 19.5 months; P = .142). The linear multivariate regression model identified an association of body mass index (BMI), MOCART 2.0 score, and number of previous knee surgeries with KOOS (R2 = 0.41; f2 = 0.69). Further analysis of the individual determinants revealed an optimal BMI range of 20 to 29 for favorable PROs at 96 months. Significant correlations of MOCART subscores with the overall KOOS were found for graft surface and structure, bony reaction, and subchondral detectable changes. Only 30% of patients with2 previous surgeries and 20% of patients with 3 previous surgeries achieved a Patient Acceptable Symptom State (χ2 = 10.93; P = .012). Conclusion: The present study shows consistently good long-term clinical outcomes after MACI with a low revision rate and high patient satisfaction. BMI and number of previous knee surgeries may influence clinical outcomes and should be considered in patient selection and education. There is a correlation between graft structure, subchondral bone changes on magnetic resonance imaging, and long-term PROMs.

The relationships between patellofemoral bone remodeling, cartilage composition, and vertical loading rate: PET/MRI in isolated patellofemoral osteoarthritis

ObjectiveLoading is invariably an important factor of consideration for understanding the causality flow and parallel existence of articular cartilage and subchondral bone changes. The goal of this study was to investigate the patterns of subregional 18NaF-SUV vs. T1p-T2 associations and vertical ground reaction force loading rates; in isolated patellofemoral-joint-osteoarthritis (PFJ-OA) patients. MethodThirty-five isolated PFJ-OA patients, with no tibiofemoral involvement, underwent simultaneous scans in a 3.0T whole-body hybrid PET-MRI scanner. MRI WORMS assessments were performed to identify/confirm isolated PFJ-OA knees from bilateral scans. T1p-T2 relaxation and SUV values were automatically computed for both trochlear and patellar cartilage and subchondral bone subregions (deep, superficial, lateral, and medial). Maximum vertical impact loading rates (Loading-RateNorm) were calculated from walking trials. Relationships were explored between SUV uptake, T1p-T2 values, and Loading-RateNorm via linear mixed-effects modeling. ResultsSignificant and complex association patterns were noted between medial and lateral bone 18NaF-SUV uptakes vs. medial and lateral cartilage sub-regional T1p and T2. SUVMean and SUVMax were positively associated with deep cartilage subregional T1pand T2 values; and negatively associated with superficial cartilage subregional T1p-T2 values in both medial and lateral regions. Both medial and lateral bone 18NaF-SUVMean and SUVMax uptakes remained positively associated with the individual gait characteristics, i.e., peak vertical impact loading rates (Loading-RateNorm). ConclusionEvidence of simultaneous, complementary, cross-sectional associations between T1p-T2 values and peak vertical loading rates with 18NaF-SUV, have been rare in the isolated PFJ-OA cohort. The clinical implications of such novel associations remain of utmost importance from a gait retraining perspective.

Microneedle-Delivered PDA@Exo for Multifaceted Osteoarthritis Treatment via PI3K-Akt-mTOR Pathway.

Osteoarthritis (OA) is marked by cartilage deterioration, subchondral bone changes, and an inflammatory microenvironment. The study introduces the Microneedle-Delivered Polydopamine-Exosome (PDA@Exo MN), a therapeutic that not only preserves cartilage and promotes bone regeneration but also improves localized drug delivery through enhanced penetration capabilities. PDA@Exo MN shows strong reactive oxygen species(ROS) scavenging abilities and high biocompatibility, fostering osteogenesis and balancing anabolic and catabolic processes in cartilage. It directs macrophage polarization from M0 to the anti-inflammatory M2 phenotype. RNA sequencing of treated chondrocytes demonstrates restored cellular function and activated antioxidant responses, with modulated inflammatory pathways. The PI3K-AKT-mTOR pathway's activation, essential for PDA@Exo's effects, is confirmed via bioinformatics and Western blot. In vivo assessments robustly validate that PDA@Exo MN prevents cartilage degradation and OA progression, supported by histological assessments and micro-CT analysis, highlighting its disease-modifying impact. The excellent biocompatibility of PDA@Exo MN, verified through histological (H&E) and blood tests showing no organ damage, underscores its safety and efficacy for OA therapy, making it a novel and multifunctional nanomedical approach in orthopedics, characterized by organ-friendliness and biosecurity.

Mesenchymal Stem Cell-Derived Exosomes as a Treatment Option for Osteoarthritis.

Osteoarthritis (OA) is a leading cause of pain and disability worldwide in elderly people. There is a critical need to develop novel therapeutic strategies that can effectively manage pain and disability to improve the quality of life for older people. Mesenchymal stem cells (MSCs) have emerged as a promising cell-based therapy for age-related disorders due to their multilineage differentiation and strong paracrine effects. Notably, MSC-derived exosomes (MSC-Exos) have gained significant attention because they can recapitulate MSCs into therapeutic benefits without causing any associated risks compared with direct cell transplantation. These exosomes help in the transport of bioactive molecules such as proteins, lipids, and nucleic acids, which can influence various cellular processes related to tissue repair, regeneration, and immune regulation. In this review, we have provided an overview of MSC-Exos as a considerable treatment option for osteoarthritis. This review will go over the underlying mechanisms by which MSC-Exos may alleviate the pathological hallmarks of OA, such as cartilage degradation, synovial inflammation, and subchondral bone changes. Furthermore, we have summarized the current preclinical evidence and highlighted promising results from in vitro and in vivo studies, as well as progress in clinical trials using MSC-Exos to treat OA.

Unveiling the Role of Sik1 in Osteoblast Differentiation: Implications for Osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative disease characterized by subchondral osteosclerosis, mainly due to osteoblast activity. This research investigates the function of Sik1, a member of the AMP-activated protein kinase family, in OA. Proteomic analysis was conducted on clinical samples from 30 OA patients, revealing a negative correlation between Sik1 expression and OA. In vitro experiments utilized BMSCs to examine the effect of Sik1 on osteogenic differentiation. BMSCs were cultured and induced toward osteogenesis with specific media. Sik1 overexpression was achieved through lentiviral transfection, followed by analysis of osteogenesis-associated proteins using Western blotting, RT-qPCR, and alkaline phosphate staining. In vivo experiments involved destabilizing the medial meniscus in mice to establish an OA model, assessing the therapeutic potential of Sik1. The CT scans and histological staining were used to analyze subchondral bone alterations and cartilage damage. The findings show that Sik1 downregulation correlates with advanced OA and heightened osteogenic differentiation in BMSCs. Sik1 overexpression inhibits osteogenesis-related markers invitro and reduces cartilage damage and subchondral osteosclerosis invivo. Mechanistically, Sik1 modulates osteogenesis and subchondral bone changes through Runx2 activity regulation. The research emphasizes Sik1 as a promising target for treating OA, suggesting its involvement in controlling bone formation and changes in the subchondral osteosclerosis.

Subchondral insufficiency fractures: overview of MRI findings from hip to ankle joint.

Subchondral insufficiency fracture (SIF) represents a potentially severe condition that can advance to osteoarthritis, with collapse of the articular surface. SIF manifests as a fracture in bone weakened by non-tumorous disease, precipitated by repetitive physiological stress, without a clear history of major trauma. It is observed along the central weight-bearing region of the femoral condyle, with a higher incidence in the medial femoral condyle, but also in other large weight-bearing synovial joints, such as the femoral head, tibial plateau, or talus.A review of the literature from the past six years was performed by searching PubMed and ScienceDirect databases, using the keywords "subchondral insufficiency fracture" and "spontaneous osteonecrosis of the knee". The inclusion criteria were scientific papers presented in the English language that reported on the magnetic resonance imaging (MRI) aspects of SIF of the lower limb.Detecting SIF at the level of the hip, knee, and ankle may present challenges both clinically and radiologically. The MRI appearance is dominated by a bone marrow edema-like signal and subchondral bone changes that can sometimes be subtle. Subchondral abnormalities are more specific than the pattern of bone marrow edema-like signal and are best shown on T2-weighted and proton-density-weighted MR images. MRI plays an important role in accurately depicting even subtle subchondral fractures at the onset of the disease and proves valuable in follow-up, prognosis, and the differentiation of SIF from other conditions. · Subchondral insufficiency fractures may affect the hip, knee, and ankle.. · Subchondral insufficiency fractures may heal spontaneously or progress to collapse.. · MRI is important for the detection, follow-up, and prognosis of subchondral insufficiency fractures.. · Differential diagnosis may include transient osteoporosis and osteonecrosis of systemic origin.. · Buturoiu MM, Ghiea S, Weber M. Subchondral insufficiency fractures: overview of MRI findings from hip to ankle joint. Fortschr Röntgenstr 2024; DOI 10.1055/a-2344-5337.

Seven-Year Longitudinal Study: Clinical Evaluation of Knee Osteoarthritic Patients Treated with Mesenchymal Stem Cells.

Background/Objectives: Numerous studies have demonstrated the safety and efficacy of intraarticular stem cell injections for treating osteoarthritic knee joints, reporting symptom reduction and pain relief within a few months of treatment. Here, we report the results of a 7-year follow-up after a single intraarticular injection of 0.5-1 × 107 autologous adipose tissue-derived mesenchymal stem cells in patients with OA (Kellgren-Lawrence grade 2 to 4). Methods: Nine patients were treated, and two patients had bilateral disease. Patients were evaluated clinically and radiologically using X-ray and MRI. A comprehensive statistical analysis was undertaken to evaluate the obtained results. Results: All clinical scores and range of motion significantly improved within the first six months after injection. At the 18-month time point, a significant improvement in cartilage structure was observed on MRI while X-ray showed no changes in subchondral bone of distal femur and proximal tibia. At the 60-month time point, the clinical scores were still improved compared to baseline, except for the range of motion, which decreased almost back to the baseline level. At 84 months, the clinical scores decreased significantly toward the baseline level, but the MRI structural characteristics of cartilage still remained significantly better than those measured at baseline. Conclusions: Adipose tissue-derived stem cell therapy has substantial long-term clinical effects on patients with knee osteoarthritis.

Unveiling the Pathophysiology of Osteoarthritis in Joint Anatomy

Background: Osteoarthritis (OA) is a prevalent and debilitating joint disorder characterized by the degeneration of articular cartilage and underlying bone. Understanding the pathophysiology of OA is essential for developing targeted therapies and improving patient outcomes. Objective: To explore the underlying pathophysiological mechanisms of osteoarthritis within the context of joint anatomy, focusing on cartilage degradation, synovial inflammation, and subchondral bone changes. Methods: This prospective study was conducted at private hospitals in Karachi from June 2022 to December 2022. Eighty patients aged 45 to 70 years, diagnosed with OA, were included. Detailed clinical evaluations were performed, including pain assessment using the Visual Analog Scale (VAS) and functional status assessment using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Radiographic analysis was conducted using the Kellgren-Lawrence grading scale. Biochemical analysis of serum and synovial fluid was performed to measure levels of collagen type II cleavage products (C2C), cartilage oligomeric matrix protein (COMP), and inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Synovial fluid and tissue samples were collected during arthroscopy or joint replacement surgery for molecular pathway analysis. Data were analyzed using SPSS version 25, with correlations and regression analyses performed to identify predictors of disease progression. Results: OA was associated with significant pain and functional impairment, with a mean pain score of 7.2 ± 1.3 on the VAS and WOMAC scores averaging 55 ± 10 for physical function and 30 ± 5 for stiffness. Radiographic analysis showed 25% of patients classified as grade II, 50% as grade III, and 25% as grade IV. Biochemical markers indicated elevated levels of C2C (serum: 150 ± 20 ng/mL; synovial fluid: 200 ± 25 ng/mL) and COMP (serum: 10 ± 2 µg/mL; synovial fluid: 15 ± 3 µg/mL). Inflammatory cytokines were also elevated (IL-1β: 50 ± 5 pg/mL; TNF-α: 75 ± 10 pg/mL; IL-6: 100 ± 12 pg/mL). A strong positive correlation (r = 0.85, p &lt; 0.01) was observed between VAS pain scores and synovial IL-1β levels. Conclusion: The pathophysiology of osteoarthritis involves a complex interplay of biomechanical, biochemical, and cellular factors. The findings from this study enhance the understanding of OA mechanisms and provide a foundation for developing more effective therapeutic strategies aimed at halting or reversing the progression of OA.

Development of primary osteoarthritis during aging in genetically diverse UM-HET3 mice

BackgroundPrimary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium.MethodsWe investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging.ResultsAged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance.ConclusionsOur study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes.

Growth hormone-receptor disruption in mice reduces osteoarthritis and chondrocyte hypertrophy

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (μCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.

Clinical and Radiological Outcomes of Cervical Disc Arthroplasty in Patients with Modic Change.

Modic change (MC) is defined as abnormalities observed in the intervertebral disc subchondral and adjacent vertebral endplate subchondral bone changes. Most studies on MC were reported in the lumbar spine and associated with lower back pain. However, MC has been rarely reported in the cervical spine, let alone in those who underwent cervical disc replacement (CDR). This study aimed to focus on MC in the cervical spine and reveal clinical and radiological parameters, especially heterotopic ossification (HO), for patients who underwent CDR. Furthermore, we illustrated the association between MC and HO. We retrospectively reviewed patients who underwent CDA from January 2008 to December 2019. The Japanese Orthopaedic Association (JOA), Neck Disability Index (NDI), and Visual Analog Scale (VAS) scores were used to evaluate the clinical outcomes. Radiological evaluations were used to conclude the cervical alignment (CL) and range of motion (ROM) of C2-7, functional spinal unit angle (FSUA), shell angle (SA), FSU height, and HO. Univariate and multivariate logistic regressions were performed to identify the risk factors for HO. The Kaplan-Meier (K-M) method was used to analyze potential risk factors, and multivariate Cox regression was used to identify independent risk factors. A total of 139 patients were evaluated, with a mean follow-up time of 46.53 ± 26.60 months. Forty-nine patients were assigned to the MC group and 90 to the non-MC group. The incidence of MC was 35.3%, with type 2 being the most common. Clinical outcomes (JOA, NDI, VAS) showed no significant difference between the two groups. The differences in C2-7 ROM between the two groups were not significant, while the differences in SA ROM and FSUA ROM were significantly higher in the non-MC than in the MC group (p < 0.05). Besides, FSU height in MC group was significantly lower than that in non-MC group. Parameters concerning CL, including C2-7, FSUA, SA, were not significantly different between the two groups. The incidence of HO and high-grade HO, respectively, in the MC group was 83.7% and 30.6%, while that in the non-MC group was 53.3% and 2.2%, and such differences were significant (p < 0.05). Multivariate logistic regression analyses and Cox regression showed that MC and involved level were significantly associated with HO occurrence (p < 0.05). No implant migration and secondary surgery were observed. MC mainly affected the incidence of HO. Preoperative MC was significantly associated with HO formation after CDR and should be identified as a potential risk factor for HO. Rigorous criteria for MC should be taken into consideration when selecting appropriate candidates for CDR.

Synovial osteoclastogenesis mediated by chondrocyte-secreted TNFα promotes TMJ condylar resorption.

Insufficient occlusal support (IOS) frequently causes subchondral bone absorption in temporomandibular joint osteoarthritis, and the underlying mechanism requires further investigation. An IOS model was established by abrading rat molars. Micro-computed tomography was used to evaluate subchondral bone changes. Osteoclastogenesis of synovium-derived macrophages (SDMs) was confirmed by TRAP staining. Cartilage-specific TNFα depletion was achieved by intra-articular injection of adeno-associated virus carrying shRNA against murine TNFα under control of collagen type II. Invitro, chondrocytes were mechanically compressed and conditioned medium (CM) was collected to detect its ability to induce osteoclastogenesis of SDMs. Synovial osteoclastogenesis and condyle resorption were observed following IOS. TNFα level was elevated in hypertrophic chondrocytes after IOS. Synovial Wnt5a level increased, but Wnt3a level decreased after IOS. Depletion of TNFα in chondrocytes alleviated the synovial osteoclastogenesis and condyle bone resorption. Invitro compression of chondrocytes potentiated TNFα expression and secretion. The CM promoted osteoclastogenesis of SDMs, which were partially prohibited by TNFα neutralizing antibody. Furthermore, inhibition of Wnt3a facilitated osteoclastogenesis, whereas inhibition of Wnt5a partially suppressed osteoclastogenesis, of SDMs cultured in CM. Chondrocyte-secreted TNFα induced by IOS is a critical regulator of synovial osteoclastogenesis and subsequent condylar resorption, partially through non-canonical Wnt5a pathway.

OSTF1 knockdown mitigates IL-1β-induced chondrocyte injury via inhibiting the NF-κB signaling pathway

Osteoarthritis (OA) is an age-related joint disease characterized by progressive heterogeneous changes in articular cartilage and subchondral bone. Osteoclast stimulating factor 1 (OSTF1) is a small intracellular protein involved in bone formation and bone resorption. However, to our best knowledge, its role in OA is still unclear. In this study, an OA rat model was established by anterior cruciate ligament transection (ALCT). OSTF1 was increased in the cartilage tissues of OA patients and OA rats. Next, the role of OSTF1 in interleukin-1β (IL-1β)-induced chondrocyte apoptosis, inflammation and extracellular matrix degradation was explored through loss of function assays. Strikingly, OSTF1 knockdown relieved IL-1β-induced chondrocyte apoptosis, with decreased cleaved caspase-3 and cleaved PARP levels. Besides, OSTF1 knockdown restrained IL-1β-induced inflammation and degradation of extracellular matrix of chondrocytes. Subsequently, the molecular mechanism of OSTF1 was explored. Transcriptomic analysis revealed the potential gene network map regulated by OSTF1 knockdown. Some differentially expressed genes (DEGs) were involved in regulating the NF-κB signaling pathway. Furthermore, our results demonstrated that OSTF1 knockdown inhibited IL-1β-activated the NF-κB signaling pathway. Ultimately, we analyzed the potential gene network map regulated by OSTF1 and its downstream NF-κB. Bioinformatics analysis showed that 18 DEGs in OSTF1-silenced chondrocytes overlapped with the NF-κB downstream targets. Collectively, our findings indicate that OSTF1 knockdown mitigates IL-1β-induced chondrocyte injury via inhibiting the NF-κB signaling pathway.

PTH treatment before cyclic joint loading improves cartilage health and attenuates load-induced osteoarthritis development in mice.

Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the subchondral bone properties to OA development. We used parathyroid hormone (PTH) to modulate bone mass before OA initiation and alendronate (ALN) to inhibit bone remodeling during OA progression. We examined the spatiotemporal progression of joint damage by combining histopathological and transcriptomic analyses across joint tissues. The additive effect of PTH pretreatment before OA initiation and ALN treatment during OA progression most effectively attenuated load-induced OA pathology. Individually, PTH directly improved cartilage health and slowed the development of cartilage damage, whereas ALN primarily attenuated subchondral bone changes associated with OA progression. Joint damage reflected early transcriptomic changes. With both treatments, the structural changes were associated with early modulation of immunoregulation and immunoresponse pathways that may contribute to disease mechanisms. Overall, our results demonstrate the potential of subchondral bone-modifying therapies to slow the progression of OA.

High-resolution magnetic resonance imaging can predict osteoarthritic progression after medial meniscus posterior root injury: randomized in vivo experimental study in a rabbit model

ImportanceThe field of meniscal root preservation has undergone significant advancement over the past decades; however, the challenge remains to fully understand whether meniscal root repair can ultimately arrest or delay osteoarthritic changes. ObjectiveTo assess longitudinal changes in articular cartilage, subchondral bone, and progression to meniscal extrusion (ME) using high-resolution magnetic resonance imaging (MRI). MethodsMedial meniscus posterior root tear was surgically induced in 39 New Zealand white rabbits. Animals were randomly assigned into three experimental groups: partial meniscectomy after root tear (PM, n ​= ​13); root tear left in situ (CT, n ​= ​13); and transtibial root repair (RR, n ​= ​13). Contralateral limbs were used as healthy controls. High resolution 4.7 Tesla MRI of the knee joint was performed at baseline, after 2-, and 4-months of post-surgery. Cartilage thickness was calculated in medial and lateral compartments. In addition, the evaluation of ME, subchondral bone edema and healing potential after root repair were assessed too. ResultsProgressive cartilage thinning, ME, and subchondral bone edema were evident in all 3 study groups after 4-months of follow-up. The mean cartilage thickness in the PM group was 0.53 ​mm (±0.050), 0.57 ​mm (±0.05) in the CT group, and 0.60 ​mm (±0.08) in the RR group. The PM group exhibited significantly higher cartilage loss when compared to the CT and RR groups (p ​< ​0.001). Moreover, progressive ME and subchondral bone edema were associated with a more severe cartilage loss at the final follow-up. ConclusionMeniscal root repair did not halt but rather reduced the progression of osteoarthritis (OA). Degenerative changes worsened at a rapid rate in the PM group compared to the RR and CT groups. Early cartilage swelling, persistent subchondral edema, and progressive ME predicted a more severe progression to knee OA in the CT and RR groups. Level of evidenceII.

Effects of intra-articular injection of platelet-rich plasma on the inflammatory process and histopathological characteristics of cartilage and synovium in animals with osteoarthritis: a systematic review with meta-analysis

BackgroundOsteoarthritis (OA) affects the entire joint, causing structural changes in articular cartilage, subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles that afflicts millions of people globally, leading to persistent pain and diminished quality of life. The intra-articular use of platelet-rich plasma (PRP) is gaining recognition as a secure therapeutic approach due to its potential regenerative capabilities. However, there is controversial clinical data regarding efficacy of PRP for OA treatment. In this context, gathering scientific evidence on the effects of PRP in treating OA in animal models could provide valuable insights into understanding its impact on aspects like cartilage health, synovial tissue integrity, and the inflammatory process in affected joints. Thus, the objective of this study was to assess the effects of PRP injections on inflammation and histopathological aspects of cartilage and synovium in animal models of OA through a comprehensive systematic review with meta-analysis.MethodsA electronic search was conducted on Medline, Embase, Web of Science, The Cochrane Library, LILACS, and SciELO databases for relevant articles published until June 2022. A random-effects meta-analysis was employed to synthesize evidence on the histological characteristics of cartilage and synovium, as well as the inflammatory process. The GRADE approach was utilized to categorize the quality of evidence, and methodological quality was assessed using SYRCLE’s RoB tool.ResultsTwenty-one studies were included in the review, with twelve of them incorporated into the meta-analysis. PRP treatment demonstrated superior outcomes compared to the control group in terms of cartilage histology (very low quality; p = 0.0002), synovium histology (very low quality; p < 0.0001), and reductions in proinflammatory markers, including IL-1 (low quality; p = 0.002), IL-6 (very low quality; p < 0.00001), and TNF-α (very low; p < 0.00001). However, PRP treatment did not yield a significant impact on PDGF-A levels (very low quality; p = 0.81).ConclusionPRP appears capable of reducing proinflammatory markers (IL-1, IL-6, TNF-α) and mitigating cartilage and synovium damage in animals with OA. However, the levels of evidence of these findings are low to very low. Therefore, more rigorous studies with larger samples are needed to improve the quality of evidence.PROSPERO registrationCRD42022250314

Phytochemicals against Osteoarthritis by Inhibiting Apoptosis.

Osteoarthritis (OA) is a chronic joint disease that causes pathological changes in articular cartilage, synovial membrane, or subchondral bone. Conventional treatments for OA include surgical and non-surgical methods. Surgical treatment is suitable for patients in the terminal stage of OA. It is often the last choice because of the associated risks and high cost. Medication of OA mainly includes non-steroidal anti-inflammatory drugs, analgesics, hyaluronic acid, and cortico-steroid anti-inflammatory drugs. However, these drugs often have severe side effects and cannot meet the needs of patients. Therefore, safe and clinically appropriate long-term treatments for OA are urgently needed. Apoptosis is programmed cell death, which is a kind of physiologic cell suicide determined by heredity and conserved by evolution. Inhibition of apoptosis-related pathways has been found to prevent and treat a variety of diseases. Excessive apoptosis can destroy cartilage homeostasis and aggravate the pathological process of OA. Therefore, inhibition of apoptosis-related factors or signaling pathways has become an effective means to treat OA. Phytochemicals are active ingredients from plants, and it has been found that phytochemicals can play an important role in the prevention and treatment of OA by inhibiting apoptosis. We summarize preclinical and clinical studies of phytochemicals for the treatment of OA by inhibiting apoptosis. The results show that phytochemicals can treat OA by targeting apoptosis-related pathways. On the basis of improving some phytochemicals with low bioavailability, poor water solubility, and high toxicity by nanotechnology-based drug delivery systems, and at the same time undergoing strict clinical and pharmacological tests, phytochemicals can be used as a potential therapeutic drug for OA and may be applied in clinical settings.

Targeted inhibition of STAT3 (Tyr705) by xanthatin alleviates osteoarthritis progression through the NF-κB signaling pathway

The transcription factor, signal transducer, and stimulator of transcription 3 (STAT3) is a potential target in osteoarthritis (OA) treatment. Although xanthatin (XA), a biologically active substance derived from Xanthium strumarium L, specifically inhibits STAT3 phosphorylation at Tyr705, the mechanism underlying its inhibitory effect on OA progression remains unclear. In this study, our objective was to explore the therapeutic effects exerted by XA on OA and the underlying molecular mechanisms. The effects of XA treatment on mouse OA models subjected to destabilization of the medial meniscus using medial collateral ligament transection, as well as on interleukin-1β (IL-1β)-induced mouse chondrocytes, were examined. Histological changes in cartilage and subchondral bone (SCB), as well as changes in the expression levels of osteophytes, cartilage degeneration- and osteoclast differentiation-related factors, and the role of XA-related signaling pathways in human cartilage tissue, were studied using different techniques. XA inhibited STAT3 phosphorylation at Tyr705 and further attenuated the activity of nuclear factor-κB (NF-κB) in chondrocytes and osteoclasts. In vitro, XA administration alleviated pro-inflammatory cytokine release, extracellular matrix catabolism, and RANKL-mediated osteoclast differentiation. In vivo, intraperitoneal injection of XA exerted a protective effect on cartilage degeneration and SCB loss. Similarly, XA exerted a protective effect on human cartilage tissue by inhibiting the STAT3/NF-κB signaling pathway. Overall, our study elucidated the therapeutic potential of XA as a small-molecule inhibitor of STAT3-driven OA progression. This discovery may help enhance innovative clinical interventions against OA.

The BMP7-Derived Peptide p[63-82] Reduces Cartilage Degeneration in the Rat ACLT-pMMx Model for Posttraumatic Osteoarthritis.

Osteoarthritis (OA) is characterized by articular cartilage erosion, pathological subchondral bone changes, and signs of synovial inflammation and pain. We previously identified p[63-82], a bone morphogenetic protein 7 (BMP7)-derived bioactive peptide that attenuates structural cartilage degeneration in the rat medial meniscal tear-model for posttraumatic OA. This study aimed to evaluate the cartilage erosion-attenuating activity of p[63-82] in a different preclinical model for OA (anterior cruciate ligament transection-partial medial meniscectomy [anterior cruciate ligament transection (ACLT)-pMMx]). The disease-modifying action of the p[63-82] was followed-up in this model for 5 and 10 weeks. Skeletally mature male Lewis rats underwent ACLT-pMMx surgery. Rats received weekly intra-articular injections with either saline or 500 ng p[63-82]. Five and 10 weeks postsurgery, rats were sacrificed, and subchondral bone characteristics were determined using microcomputed tomography (µCT). Histopathological evaluation of cartilage degradation and Osteoarthritis Research Society International (OARSI)-scoring was performed following Safranin-O/Fast Green staining. Pain-related behavior was measured by incapacitance testing and footprint analysis. Histopathological evaluation at 5 and 10 weeks postsurgery showed reduced cartilage degeneration and a significantly reduced OARSI score, whereas no significant changes in subchondral bone characteristics were found in the p[63-82]-treated rats compared to the saline-treated rats. ACLT-pMMx-induced imbalance of static weightbearing capacity in the p[63-82] group was significantly improved compared to the saline-treated rats at weeks 5 postsurgery. Footprint analysis scores in the p[63-82]-treated rats demonstrated improvement at week 10 postsurgery. Weekly intra-articular injections of p[63-82] in the rat ACLT-pMMx posttraumatic OA model resulted in reduced degenerative cartilage changes and induced functional improvement in static weightbearing capacity during follow-up.