The chondrocyte "mechanome": Activation of the mechanosensitive ion channels TRPV4 and PIEZO1 drives unique transcriptional signatures.

The mechanosensitive ion channels Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 transduce physiologic and supraphysiologic magnitudes of mechanical signals in the chondrocyte, respectively. TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remain to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes and also exhibit unique co-regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)-1-responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. These findings emphasize the presence of a broad "mechanome" with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.

Is There a Need for an Exogenous Activator Along with PRP for Early Knee Osteoarthritis? A Triple-Blinded Randomized Control Trial.

Background: In addition to other variables associated with PRP injections for Knee Osteoarthritis (OA), some confusion exists about the role of exogenous activators. The current study looks at matched groups getting PRP injections with or without activator (Calcium gluconate) in early knee OA patients. Methods: Patients of early OA knee meeting inclusion criteria were randomly divided into 2 groups; Group A (43 patients) received 8 ml PRP injection alone, and Group B (48 patients) received 8 ml PRP along with 2 ml Calcium gluconate as activator. The patients were evaluated at baseline, 6 weeks, 3 months and 6 months for WOMAC Pain and Total WOMAC scores; secondary variables assessed were VAS score and patient satisfaction. Results: The baseline characteristics of both groups were comparable. Leucocyte-depleted PRP with 5 times concentration and average absolute platelet numbers of 7.144 billion per knee was injected. Mean Pain WOMAC scores decreased in both groups from baseline (group A-8.68, group B-9.09) to final follow-up (group A-4.67, group B-5.11). Similarly, Mean Total WOMAC scores decreased from baseline (group A-37.81, group B-37.41) to (group A-21, group B-21.36) at the final follow-up in both groups. There was no significant difference between both groups, and both showed similar trends. Similar findings were noted for VAS scores. Patient satisfaction was also not different (group A, 90.69%, group B, 89.58%) at the end of 6 months. Conclusion: Our study concluded doubtful role of adding exogenous activator to PRP preparation. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-024-01159-7.

Chondroprotective Effects of a Single PRP Injection in a Spontaneous Osteoarthritis Model of Dunkin Hartley Guinea Pig: An Immunohistochemical Analysis.

Purpose of the Study: The evaluation of anti-apoptotic and chondroprotective properties of a single injection of PRP using immunohistochemistry (IHC). Methods: This was a placebo-controlled blinded experimental study. Ten healthy Dunkin Hartley guinea pigs were selected. One knee of each animal was injected with a single injection of PRP (Group A); the contralateral knee acted as a control and was injected with a single injection of normal saline (Group B). These groups were further divided into A3 and B3 based on the timeline of animal sacrifice (3 months) and A6 and B6 (6 months). The formalin-preserved articular cartilage blocks were subjected to IHC to stain Aggrecan, Caspase-3, and Collagen-2. Results: The mean IHC score was significantly low for Caspase-3 (p-0.029) in intervention group (A3) in comparison to placebo control group (B3) pointing towards decreased apoptosis. The mean IHC values were significantly higher for Collagen II (p-0.011) for intervention group (A6) in contrast to control group (B6); values were also significantly low for Caspase-3 (p-0.029) in A6 as compared to B6. The mean Caspase-3 values were significantly higher in A6 as compared to A3 (p-0.029). Conclusion: The impact of a solitary injection of PRP on upregulation of anabolic pathways inside cartilage is relatively slower as compared to its effect on downregulation of apoptotic pathways. Even a single PRP injection holds the potential to change cartilage microenvironment, but the effects are not long lasting.

Bone Marrow Aspirate Concentrate for Treatment of Primary Knee Osteoarthritis: A Prospective, Single-Center, Non-randomized Study with 2-Year Follow-Up.

Introduction: Knee osteoarthritis (OA) is a widespread, disabling condition with no intervention to fully restore cartilage or halt progression. Bone marrow aspirate concentrate (BMAC), an autologous product from bone marrow aspiration, has shown promise as a regenerative therapy due to its cell composition and chondrogenic effects. Our study aims to assess the functional outcomes, including pain, function, satisfaction, and complications post-BMAC injection in knee OA patients. Materials and Methods: In this prospective, single-center study, 63 patients with grade II-III knee OA (Kellgren-Lawrence (K-L) scale) unresponsive to conservative management underwent BMAC injection. The procedure involved bone marrow aspiration from the anterior iliac crest, processing to obtain a concentrate, followed by intra-articular injection. Patients were followed for 24 months, assessing outcomes using the Visual Analog Scale (VAS), International Knee Documentation Committee (IKDC) score, and MOCART 2.0 score. Results: The cohort, with a slight female predominance and predominantly aged 41-50 years, majorly comprised K-L grade III OA patients. BMAC treatment resulted in significant improvements in VAS pain scores, IKDC functional scores, and MOCART 2.0 scores over the 24-month follow-up. Conclusion: BMAC injection provides significant improvement in both pain and functional outcomes at mid-term follow-up in patients with mild-to-moderate OA of the knee. Further high-quality, adequately powered, multi-center, prospective, double-blinded, randomized controlled trials with longer follow-up are necessary to justify the routine clinical use of BMAC for treatment of patients suffering with knee OA.

Safety and Efficacy of Bone-Marrow Aspirate Concentrate in Hip Osteoarthritis: A Systematic Review of Current Clinical Evidence.

Introduction: Hip osteoarthritis (OA) is one of the leading causes of disability and morbidity worldwide. It is estimated to affect 9.2% individuals globally with age over 45 years. Conventional treatment modalities have limitations and side-effects. To overcome these limitations, over the last decade, there has been an increased interest in the use of orthobiologics derived from autologous sources including platelet-rich plasma (PRP), bone-marrow aspirate concentrate (BMAC) and adipose tissue derived formulations. This review qualitatively presents the in-vitro, pre-clinical, clinical and on-going clinical studies exploring the safety and efficacy of BMAC for management of hip OA. Materials and methods: The electronic database search was done through PubMed, Embase, Web of Science, Scopus, ProQuest and Google Scholar till February 2024. The search terms used were "osteoarthritis" OR "hip osteoarthritis" OR "orthobiologics" OR "efficacy or use of orthobiologic treatment" OR "bone-marrow concentrate" OR "bone-marrow aspirate concentrate", AND "BMAC". The inclusion criteria were clinical studies of any level of evidence written in the English language, published till February 2024, evaluating the safety and efficacy of intra-articular administration of BMAC for the management of hip OA. Results: A total of 5 studies were included in this review for qualitative data synthesis. The total number of patients who participated in the study was 182, ranging from 4 to 112 in a single study. No adverse events were reported throughout the duration of the study. In addition, intra-articular administration of BMAC led to reduced pain, and improved function and overall quality of life (QoL). Conclusion: The results from this review demonstrated that administration of BMAC is safe and potentially efficacious in terms of reducing pain, improving function and overall QoL of patients with hip OA in short- and mid-term average follow-up based on the included studies. Nonetheless, more adequately powered, multi-center, prospective, double-blind, non-randomized and randomized controlled trials with long-term follow-up are warranted to establish long-term safety and efficacy of BMAC for management of hip OA and justify its routine clinical use.

Exosomes in Osteoarthritis: A Review on Their Isolation Techniques and Therapeutic Potential.

Background: Exosomes are the smallest extracellular vesicles (30-150 nm) secreted by all cell types, including synovial fluid. However, because biological fluids are complex, heterogeneous, and contain contaminants, their isolation is difficult and time-consuming. Furthermore, the pathophysiology of osteoarthritis (OA) involves exosomes carrying complex components that cause macrophages to release chemokines and proinflammatory cytokines. This narrative review aims to provide in-depth insights into exosome biology, isolation techniques, role in OA pathophysiology, and potential role in future OA therapeutics. Methods: A literature search was conducted using PubMed, Scopus, and Web of Science databases for studies involving exosomes in the osteoarthritis using keywords "Exosomes" and "Osteoarthritis". Relevant articles in the last 15 years involving both human and animal models were included. Studies involving exosomes in other inflammatory diseases were excluded. Results: Despite some progress, conventional techniques for isolating exosomes remain laborious and difficult, requiring intricate and time-consuming procedures across various body fluids and sample origins. Moreover, exosomes are involved in various physiological processes associated with OA, like cartilage calcification, degradation of osteoarthritic joints, and inflammation. Conclusion: The process of achieving standardization, integration, and high throughput of exosome isolation equipment is challenging and time-consuming. The integration of various methodologies can be employed to effectively address specific issues by leveraging their complementary benefits. Exosomes have the potential to effectively repair damaged cartilage OA, reduce inflammation, and maintain a balance between the formation and breakdown of cartilage matrix, therefore showing promise as a therapeutic option for OA.

Growth Factor Concentrate (GFC) for the Management of Osteoarthritis of the Knee: A Systematic Review.

Introduction: The knee is the most commonly affected joint in osteoarthritis (OA), affecting millions of people worldwide. Knee OA significantly impacts the activities of daily living (ADL) along with affecting overall quality of life of patients (QoL), thereby leading to substantial socio-economic burden. Conservative therapies are prioritized, resorting to surgery only when needed. However, these traditional approaches have limitations. Regenerative medicine, involving the use of orthobiologics, including autologous peripheral blood-derived orthobiologics such as growth factor concentrate (GFC), has evolved and shown potential for managing knee OA. The primary goal of this review is to summarize the results of in vitro, preclinical and clinical studies involving GFC for the management of knee OA. Methods: Multiple databases (PubMed, Scopus, Google Scholar, Web of Science and Embase) were searched applying terms for the intervention 'GFC' and treatment 'knee OA' for the studies published in the English language to March 10, 2024. Results: Only three clinical studies met our pre-defined criteria and were included in this review. Conclusion: Intra-articular administration of GFC is safe and potentially efficacious to manage OA of the knee. More, adequately powered, multi-center, prospective, RCTs are warranted to demonstrate the long-term effectiveness of GFC in patients suffering from mild-to-moderate knee OA and to justify its routine clinical use. Further studies evaluating the efficacy of GFC compared to other orthobiologics are also required to allow physicians/surgeons to choose the optimal orthobiologic for the treatment of OA of the knee.

Metabolomics in Osteoarthritis Knee: A Systematic Review of Literature.

Introduction: Osteoarthritis (OA) is a common degenerative disorder of the synovial joints and is usually an age-related disease that occurs due to continuous wear and tear of the cartilage in the joints. Presently, there is no proven medical management to halt the progression of the disease in the early stages. The purpose of our systematic review is to analyze the possible metabolites and metabolic pathways that are specifically involved in OA pathogenesis and early treatment of the disease. Materials and Methods: The articles were collected from PubMed, Cochrane, Google Scholar, Embase, and Scopus databases. "Knee", "Osteoarthritis", "Proteomics", "Lipidomics", "Metabolomics", "Metabolic Methods", and metabolic* were employed for finding the articles. Only original articles with human or animal OA models with healthy controls were included. Results: From the initial screening, a total of 458 articles were identified from the 5 research databases. From these, 297 articles were selected in the end for screening, of which 53 papers were selected for full-text screening. Finally, 50 articles were taken for the review based on body fluid: 6 urine studies, 15 plasma studies, 16 synovial fluid studies, 11 serum studies, 4 joint tissue studies, and 1 fecal study. Many metabolites were found to be elevated in OA. Some of these metabolites can be used to stage the OA Three pathways that were found to be commonly involved are the TCA cycle, the glycolytic pathway, and the lipid metabolism. Conclusion: All these studies showed a vast array of metabolites and metabolic pathways associated with OA. Metabolites like lysophospholipids, phospholipids, arginine, BCCA, and histidine were identified as potential biomarkers of OA but a definite association was not identified, Three pathways (glycolytic pathway, TCA cycle, and lipid metabolic pathways) have been found as highly significant in OA pathogenesis. These metabolic pathways could provide novel therapeutic targets for the prevention and progression of the disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-024-01169-5.

The effect of aquatherapy on pain intensity and performance in patients with osteoarthritis.

Introduction and Aim: Osteoarthritis (OA) is a noninflammatory joint disease. If OA of the knee causes pain, decreased muscle strength and joint stiffness, exercise therapy is one of the most effective treatments for the disease. The aim of the present study was to evaluate the effect of aquatherapy on pain intensity and performance in women with OA with the assumption that it causes weightlessness. Methods: This is a quasiexperimental study. The sample size included 60 people who were randomly divided into experimental and control groups. The visual analogue scale was used to assess pain and timed up and go test (TUG), 30 Second Sit to Stand Test (30-S-CS), and 40-meter fast-paced walk test (40 MW) were used to assess performance. Data analysis was carried out using SPSS ver. 22. Results: The results of the present study showed a decrease in pain intensity from moderate to mild intensity. Also, physical performance dimensions in patients with OA were improved, so that the average TUG increased from 14.06 to 8.8 s. The average S-CS frequency increased from 4.86 to 8.4 s and 90 MW decreased from the average 93.43 to 72.66 s. Discussion and Conclusion: Lower limb muscle strength, and physical performance can be improved and pain intensity can be reduced in patients with OA by performing aquatherapy three times a week for 8 weeks.

Effect of platelet-rich plasma injections versus placebo on pain and quality of life in patients with hip osteoarthritis: A double-blind, randomized clinical trial.

Objectives: This study aims to compare the efficacy of intra-articular platelet-rich plasma (PRP) injections over a saline placebo in terms of reduction of pain and impact on quality of life among patients with hip osteoarthritis. Patients and methods: A total of 60 patients (29 males, 31 females, mean age: 57.9±7.3 years; range, 47 to 69 years) with known hip osteoarthritis of Kellgren-Lawrance (KL) Grades 2/3 were randomized into placebo (n=30) and PRP groups (n=30) between June 2014 and June 2015. Both groups received intra-articular injections into the hip joint under ultrasound guidance for three consecutive weeks. The patients were followed for six months, and pain reduction was assessed using the Visual Analog Scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire, and Short Form Health Survey-36 (SF-36). Results: Intra-articular PRP treatment showed no advantage over a saline placebo in terms of VAS scores during activity. Both groups showed a significant improvement in VAS activity scores at one and six months. The placebo group showed improvements in VAS resting scores, whereas the PRP group did not. Both groups showed no improvement in WOMAC-total scores. Both groups showed no significant improvement across most SF-36 domains with the exception of improved physical role functioning at one month and general health at one and six months in the placebo group. Conclusion: Intra-articular injections of PRP show no significant difference compared to a saline placebo over a period of six months on pain, function, and quality of life scores in patients with hip osteoarthritis.

The effect of combined hydrolyzed type 2 collagen, methylsulfonylmethane, glucosamine sulfate and chondroitin sulfate supplementation on knee osteoarthritis symptoms.

Objectives: This study aimed to evaluate the effects of the combined hydrolyzed type 2 collagen, methylsulfonylmethane (MSM), glucosamine sulfate (GS), and chondroitin sulfate (CS) supplement on knee pain intensity in patients with knee osteoarthritis (OA). Patients and methods: This multicenter, observational, noninterventional study included 98 patients (78 females, 20 males; mean age: 52.8±6.5 years; range, 40 to 64 years) who had Grade 1-3 knee OA between May 2022 and November 2022. The patients were prescribed the combination of hydrolyzed type 2 collagen, MSM, GS, and CS as a supplement for knee OA. The sachet form of the combined supplement containing 1250 mg hydrolyzed type 2 collagen, 750 mg MSM, 750 mg GS, and 400 mg CS was used once daily for two consecutive months. Patients were evaluated according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analog Scale (VAS)-pain, and Health Assessment Questionnaire (HAQ). Patients were scheduled to visit for follow-up four weeks (Visit 2) and eight weeks (Visit 3) after Visit 1 (baseline; day 0 of the study). Results: For the VAS-pain, WOMAC, WOMAC-subscale, and HAQ scores, the differences in improvement between the three visits were significant (p<0.001 for all). The patient compliance with the supplement was a median of 96.77%, both for Visit 2 and Visit 3. Conclusion: The combination of hydrolyzed type 2 collagen, MSM, GS, and CS for eight weeks in knee OA was considered an effective and safe nutritional supplement.

Autologous bone grafting in combination with autologous chondrocyte implantation yields favourable outcomes in the treatment of osteochondral defects of the knee: A systematic literature review.

PURPOSE: This study addresses the gap in the current literature by evaluating the combined treatment of autologous bone grafting and autologous chondrocyte implantation (ABCI) for osteochondral defects of the knee. It aims to evaluate clinical outcomes against methodological quality and to summarize histological results and surgical techniques. METHODS: A thorough search was conducted across Pubmed, Cochrane and Embase databases. Studies reporting clinical outcomes of ABCI for osteochondral defects of the knee were included. Patient-reported outcome measures (PROMs), failure rates, methodological quality and potential conflicts of interest were evaluated. Histological results and surgical techniques were summarized. RESULTS: Eighteen studies with 344 analyzed patients met the eligibility criteria for inclusion. All studies showed a significant improvement (p < 0.05) across different PROMs (subjective International Knee Documentation Committee score, Cincinnati Knee Rating System, Visual Analogue Scale, Lysholm Score, Tegner Activity Scale, Knee injury and Osteoarthritis Outcome Score and Knee Society Score) compared to the preoperative status. Failure rates ranged from 0% to 17.6%, with a mean follow-up of 73.2 months (range: 9.0-143.6 months). Methodological quality was low to medium, including only one comparative study. Six studies reviewed reported a potential conflict of interest. The histological assessment showed effective bonding between autologous chondrocytes and bone graft. A large degree of variability was observed in the operative technique used. CONCLUSION: The current literature suggests that ABCI yields good clinical outcomes at mid- to long-term follow-up with favourable histological results for osteochondral defects of the knee. However, future research should focus on high-quality comparative studies to better guide treatment choices. Introducing ABCI as the standard abbreviation may enhance clarity in future research. LEVEL OF EVIDENCE: Level IV.

Effects of the combination of various pharmacological treatments and exercise on knee osteoarthritis: a systematic review and network meta-analysis.

Purpose: The combination of pharmacological and non-pharmacological interventions is strongly recommended by current guidelines for knee osteoarthritis. However, few systematic reviews have validated their combined efficacy. In this study, we investigated the effects of the combination of pharmacological agents and exercise on knee osteoarthritis. Methods: Randomized controlled trials that investigated the efficacy of pharmacological agents combined with exercise for knee osteoarthritis were searched in PubMed, Embase, and Cochrane Library up to February 2024. The network meta-analysis was performed within the frequentist framework. Standardized mean difference (SMD) with 95% CI was estimated for pain and function. Grading of recommendations, assessment, development, and evaluations were used to evaluate the certainty of evidence. Results: In total, 71 studies were included. The combination therapy outperformed pharmacological or exercise therapy alone. Among the various pharmacological agents combined with exercise, mesenchymal stem cell injection was ranked the best for short-term pain reduction (SMD: -1.53, 95% CI: -1.92 to -1.13, high certainty), followed by botulinum toxin A, dextrose, and platelet-rich plasma. For long-term pain relief, dextrose prolotherapy was the optimal (SMD: -1.76, 95% CI: -2.65 to -0.88, moderate certainty), followed by mesenchymal stem cells, platelet rich in growth factor, and platelet-rich plasma. Conclusion: Exercise programs should be incorporated into clinical practice and trial design. For patients undergoing exercise therapies, mesenchymal stem cell, dextrose, platelet-rich plasma, platelet rich in growth factor, and botulinum toxin A may be the optimal agents.

Adipocyte enhancer binding protein 1 knockdown alleviates osteoarthritis through inhibiting NF-κB signaling pathway-mediated inflammation and extracellular matrix degradation.

Inflammation promotes the degradation of the extracellular matrix, which contributes to the development of osteoarthritis (OA). Adipocyte enhancer binding protein 1 (AEBP1) participates in multiple pathological processes related to inflammatory diseases. However, the role of AEBP1 in OA development is unknown. We found a higher AEBP1 expression in articular cartilage of OA patients (n = 20) compared to their normal controls (n = 10). Thus, we inferred that AEBP1 might affect OA progression. Then mice with destabilization of the medial meniscus (DMM) surgery and chondrocytes with IL-1ß treatment (10 ng/mL) were used to mimic OA. The increased AEBP1 expression was observed in models of OA. AEBP1 knockdown in chondrocytes reversed IL-1ß-induced inflammation and extracellular matrix degradation, which was mediated by the inactivation of NF-κB signaling pathway and the increased IκBα activity. Co-immunoprecipitation assay indicated the interaction between AEBP1 and IκBα. Importantly, IκBα knockdown depleted the protective role of AEBP1 knockdown in OA. Moreover, AEBP1 knockdown in mice with OA showed similar results to those in chondrocytes. Collectively, our findings suggest that AEBP1 knockdown alleviates the development of OA, providing a novel strategy for OA treatment.

The predictors to self-reported and performance-based physical function in knee osteoarthritis patients: a cross-sectional study.

Background: Osteoarthritis (OA) knee patients have limited ability in physical function, or difficulties with physical tasks and activities may develop disability. This study aimed to observe the predictors of self-reported and performance-based physical function in patients with knee OA by analyzing the impacts of demographic, pathological, and muscle impairment factors. Methods: 135 knee OA patients participated in this study to complete self-reported questionnaires using Knee Injury and Osteoarthritis Outcome Score (KOOS). When measuring performance-based physical function, a 6-meter gait speed (6MGS) test was measured to evaluate their mobility, and a 5-time Sit-to-Stand test (5STS) was assessed to evaluate their balance. Pain intensity, knee extensor and flexor muscle strength, age, body mass index (BMI), durations of symptoms, and radiographic severity were also collected. Spearman correlation and stepwise multiple linear regression were used to explore the association and predictors in self-reported and performance-based physical function. Results: BMI and durations of symptoms did not indicate any significant correlation with either self-reported or performance-based physical function. Age is significantly negatively associated with 6MGS (r 2 = -0.383, p < 0.01), while knee extensor muscle strength has a moderate correlation with 5STS (r 2 = -0.528, p < 0.01). In the stepwise multiple linear regression models, pain intensity (ß = 0.712, p < 0.001), knee flexor muscle strength (ß = 0.112, p = 0.042) were significantly associated with self-reported physical function in daily activities and contributed to 55.0% of the variance in KOOS-PF score. Knee muscle strength, including knee extensor (5STS: ß = -0.428, p < 0.001) and flexor muscle strength (6MGS: ß = 0.367, p < 0.001), were the main predictors with performance-based physical function. Conclusion: Pain intensity was the leading risk factor of self-reported physical function, and knee flexor muscle strength contributed as well. The severity of knee OA, durations of symptoms and BMI did not contribute to physical function. However, knee extensor and flexor muscle strength were the main predictors of performance-based performance. Our results show that strengthening of weak knee muscles in both quadriceps and hamstring muscle strength should be considered a priory consideration in knee OA no matter if people are in the early or end-stage of knee OA.

Sexual dimorphism in peri-articular tissue anatomy - More keys to understanding sex-differences in osteoarthritis?

Objective: Osteoarthritis prevalence differs between women and men; whether this is the result of differences in pre-morbid articular or peri-articular anatomical morphotypes remains enigmatic. Albeit sex within humans cannot be reduced to female/male, this review focusses to the sexual dimorphism of peri-articular tissues, given lack of literature on non-binary subjects. Methods: Based on a Pubmed search and input from experts, we selected relevant articles based on the authors' judgement of relevance, interest, and quality; no "hard" bibliometric measures were used to evaluate the quality or importance of the work. Emphasis was on clinical studies, with most (imaging) data being available for the knee and thigh. Results: The literature on sexual dimorphism of peri-articular tissues is reviewed: 1) bone size/shape, 2) subchondral/subarticular bone, 3) synovial membrane and infra-patellar fad-pad (IPFP), 4) muscle/adipose tissue, and 5) peri-articular tissue response to treatment. Conclusions: Relevant sex-specific differences exist for 3D bone shape and IPFP size, even after normalization to body weight. Presence of effusion- and Hoffa-synovitis is associated with greater risk of incident knee osteoarthritis in overweight women, but not in men. When normalized to bone size, men exhibit greater muscle, and women greater adipose tissue measures relative to the opposite sex. Reduced thigh muscle specific strength is associated with incident knee osteoarthritis and knee replacement in women, but not in men. These observations may explain why women with muscle strength deficits have a poorer prognosis than men with similar deficits. A "one size/sex fits all" approach must be urgently abandoned in osteoarthritis research.

Micro-current stimulation could inhibit IL-1ß-induced inflammatory responses in chondrocytes and protect knee bone cartilage from osteoarthritis.

This study aimed to evaluate the inhibitory effects of micro-current stimulation (MCS) on inflammatory responses in chondrocytes and degradation of extracellular matrix (ECM) in osteoarthritis (OA). To determine the efficacy of MCS, IL-1ß-treated chondrocytes and monosodium iodoacetate (MIA)-induced OA rat model were used. To evaluate the cytotoxicity and nitric oxide (NO) production in SW1353 cells, the presence or absence of IL-1ß treatment or various levels of MCS were applied. Immunoblot analysis was conducted to evaluate whether MCS can modulate IL-1R1/MyD88/NF-κB signaling pathway and various indicators involved in ECM degradation. Additionally, to determine whether MCS alleviates subchondral bone structure destruction caused by OA, micro-CT analysis, immunoblot analysis, and ELISA were conducted using OA rat model. 25 and 50 µA levels of MCS showed effects in cell proliferation and NO production. The MCS group with IL-1ß treatment lead to significant inhibition of protein expression levels regarding IL-1R1/MyD88/NF-κB signaling and reduction of the nucleus translocation of NF-κB. In addition, the protein expression levels of MMP-1, MMP-3, MMP-13, and IL-1ß decreased, whereas collagen II and aggrecan increased. In animal results, morphological analysis of subchondral bone using micro-CT showed that MCS induced subchondral bone regeneration and improvement, as evidenced by increased thickness and bone mineral density of the subchondral bone. Furthermore, MCS-applied groups showed decreases in the protein expression of MMP-1 and MMP-3, while increases in collagen-II and aggrecan expressions. These findings suggest that MCS has the potential to be used as a non-pharmaceutical method to alleviate OA.

The effects of medial soft tissue release for varus deformity during medial open wedge supramalleolar osteotomy: a cadaveric study.

This study was performed to investigate the effects of fibular osteotomy and release of medial soft tissues including posterior tibial tendon (PTT), and deep deltoid ligaments, which act as medial stabilizing structures in medial open wedge SMO. Twelve fresh frozen human legs were obtained and disarticulated below the knee. Experiments were conducted in four steps. First, medial open wedge tibial osteotomy was performed. Second, fibular osteotomy was performed in an inferomedial direction at the same level as the tibial osteotomy. Third, the deep deltoid ligament was released from tibial attachments. Forth, total tenotomy of the PTT was performed behind the medial malleolus. After finishing each step, contact area and peak and mean pressures were measured in the tibiotalar and talofibular joints. Fibular osteotomy after medial open wedge SMO significantly decreased mean pressure in the tibiotalar joint, mean and peak pressures in the talofibular joint. Medial soft tissue release resulted in a remarkable lateral shift and decreased tibiotalar joint loading. However, no remarkable change was observed in the tibiotalar joint during releasing medial soft tissues. The overall peak pressure distribution tended to shift more laterally compared to the value of normal alignment. In conclusion, concomitant fibular osteotomy and release of the deltoid ligament and PTT provide a useful means of minimizing tibiotalar joint stress. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-024-00370-7.

Simultaneous Concurrent Bilateral Total Knee Replacement in a Patient With Bilateral Lipoma Arborescens With End-Stage Osteoarthritis.

A 78-year-old Thai male presented with chronic bilateral knee pain and swelling. X-ray imaging revealed osteoarthritis in both knees, with a suspicious soft tissue shadow. Magnetic resonance imaging suggested lipoma arborescens (LA). The patient underwent LA excision with a complete synovectomy, followed by simultaneous bilateral total knee arthroplasty (SBTKA). Pathological examination confirmed LA. At the 2-year follow-up, the patient reported no complications, adverse outcomes, or recurrence. The intervention improved joint function and pain relief, allowing for early ambulation and full weight-bearing post-surgery. This case highlights the success of complete synovectomy with SBTKA, addressing bilateral knee pathology concurrently. The combined approach reduced operative time and significantly improved joint function and pain relief, emphasizing the benefits of timely surgical intervention and suggest potential advantages of SBTKA for optimal patient outcomes.

Topical Diclofenac Reduces Joint Synovitis in Hand Osteoarthritis: A Pilot Investigation Using Fluorescent Optical Imaging.

Purpose: Synovitis, the inflammation of joint synovia, is a prominent feature of osteoarthritis (OA) manifested by enhanced synovial vascularity, endothelial leakage, and perivascular oedema. In this pilot study, we assessed the effect of topical diclofenac in hand OA (HOA) using the established semi-quantitative methods Magnetic Resonance Imaging (MRI) and Ultrasonography (US), and compared them with Fluorescent Optical Imaging (FOI), an emerging imaging modality. Patients and Methods: Ten patients with symptomatic and diagnosed HOA used topical diclofenac for 14 days, with FOI, MRI, US, and subjective pain assessed at Baseline and after 7 (Day 8), and 14 (Day 15) days of treatment. Changes in synovitis were assessed for all 10 joints of the hand (via sum scores), and separately for the two joints most affected by synovitis. A new, fully quantitative approach for objective synovitis assessment based on the FOI images was also developed and applied. Results: The semi-quantitative analysis of the sum scores showed a small decrease in synovitis throughout the treatment duration across the different imaging modalities. The effect of the treatment was more prominent on the two most affected joints, with a synovitis reduction vs Baseline of 21.1% and 34.2% on Day 8 and Day 15, respectively, in the FOI. The quantitative FOI pixel analysis further strengthened the evidence for this effect, with observed reduction of 17.8% and 42.4% for Days 8 and 15, respectively. A similar trend was observed for subjective pain perception, with a reduction of 7.2 and 13.3 mm on Days 8 and 15. Conclusion: This pilot study evidenced the effect of topical diclofenac on reducing synovitis in hand OA in semi- and fully quantitative analyses, with the effect being stronger in the most affected joints. Further, supporting studies are needed to probe the accuracy of the quantitative pixel analysis of FOI images.