Connective Tissue Research最新文献

Aging is the largest risk factor for the development of osteoarthritis (OA), a major contributor to increased years lived with disability. This review reflects on how age-related changes relevant to OA have been measured at various length scales. Key discoveries include increased chondrocyte DNA damage with age and the disruption of matrix homeostasis by cellular senescence. Epigenetic clocks have yet to show predictive value for OA, while transcriptomic changes and miRNA profiles are linked to aging and senescence. Protein biomarkers have gained traction in the context of post-traumatic OA and may also be useful in understanding risk profiles for age-related OA. Post-translational modifications provide insights into protein aging and the rate of matrix turnover at different joint sites. Non-enzymatic crosslinks also increase with age and may be responsible for changes to the mechanical properties of joint tissues. Finally, the walking speed declines with age and predicts incident OA. Despite these advances, more research is needed on age-related changes in tissues beyond cartilage. Efforts should be directed toward identifying biomarkers of aging that can integrate large studies on genetic risk factors with the deep phenotyping done in longitudinal cohort OA studies. Early intervention is crucial for treating OA and other age-related diseases, highlighting the importance of validating sensitive and predictive biomarkers that could support new treatment paradigms. Finally, reversing at least some aspects of age-related decline may be critical for improving joint function. Promising approaches include effective delivery of targeted senolytics and the use of partial reprogramming to rejuvenate chondrocytes.

Osteoarthritis (OA) is a progressive joint disorder that leads to pain and disability for millions of people worldwide. Post-traumatic OA (PTOA), a form of OA, arises secondary to joint injury and often impacts younger individuals. Among the most common joint injuries leading to disrupted joint homeostasis and PTOA is anterior cruciate ligament (ACL) rupture. Even with successful surgical stabilization, the risk of developing PTOA persists due to several factors, including altered biology that contributes to disease progression. Recent research into the biology of ACL injuries has advanced our understanding of the mechanisms by which PTOA develops, including the inflammatory pathways involved, the expression of biomarkers specific to ACL injuries, and their interaction with factors such as the chronicity of the injury. Evidence suggests that homeostatic balance of anabolic and catabolic processes in the knee is disturbed after ACL tears, triggering a catabolic and degenerative phenotype, ultimately leading to premature joint degeneration, pain, and disability. Several key knowledge gaps exist, such as the determinants of the transition from acute to chronic inflammation, inter-patient variability in inflammatory responses, and influence of systemic factors on disease development. PTOA research faces numerous challenges, including protracted nature of the disease, the complexity of joint biology, and difficulties in translating molecular discoveries into clinical practice. Future research should prioritize improving biomarker precision for early detection, developing targeted therapies, and leveraging emerging technologies like machine learning to personalize treatment. This approach will enhance our understanding of the biological basis of PTOA resulting from ACL injuries and identify opportunities to mitigate the long-term consequences of these injuries.

Knee osteoarthritis (OA) is a debilitating condition with limited treatment options beyond symptom management or total knee arthroplasty (TKA). For younger patients, TKA presents challenges, including higher failure rates and revision surgeries. Knee joint distraction (KJD) has emerged as a promising joint-preserving alternative for end-stage knee OA, demonstrating significant improvements in pain, function, and quality of life in clinical trials and clinical practice. Almost 20 years of research has highlighted KJD's capacity to delay or prevent TKA by promoting cartilage and subchondral bone repair through whole-joint remodeling. Recent studies, including a multicenter trial with a purpose-built distraction device, confirm the treatment's efficacy and durability, with benefits lasting up to 10 years. However, long-term outcomes remain limited, and variability in patient response underscores the need for refined predictive tools. Challenges include the high incidence of pin tract infections during treatment and integrating KJD into routine clinical practice, as highlighted by limited trial enrollment in the UK KARDS trial and variability in healthcare system compatibility. Future research should focus on minimizing complications, improving patient selection through advanced imaging and biomarker analyses, and further understanding the mechanisms underlying KJD-induced joint remodeling. Large-scale trials like the ongoing Dutch GODIVA study are poised to provide robust evidence for KJD's broader adoption, implementation, and reimbursement in healthcare systems. With continued advancements, KJD holds the potential to transform the management of knee OA, offering a viable alternative to TKA for younger patients and addressing a critical unmet need in OA care.

Osteoarthritis (OA) is a chronic degenerative disease of the joint, involving cartilage degradation, synovial inflammation, and subchondral bone remodeling. Extracellular vesicles (EVs)-membrane-bound particles released by cells and have emerged as key mediators of intercellular communication in joint homeostasis and OA pathogenesis. EVs facilitate crosstalk between chondrocytes, synovial fibroblasts, and mesenchymal stem cells (MSCs), influencing joint health and disease progression. In OA, EV cargo: including proteins, miRNAs, and lipids, undergoes pathological changes that promote inflammation, matrix degradation, senescence, and calcification. Recent studies demonstrate that OA-derived EVs can induce catabolic and pro-inflammatory responses in recipient cells, while EVs from therapeutic sources such as MSCs, exhibit chondroprotective and anti-inflammatory effects in preclinical models. Additionally, EV surface markers and cargo profiles correlate with OA severity and pain, supporting their utility as minimally invasive biomarkers for early diagnosis and patient stratification. Cross-species comparisons suggest that EV signatures may be conserved, highlighting their translational potential in both human and veterinary medicine. However, the field is limited by variability in EV isolation and characterization methods, which hampers reproducibility and clinical application. To advance the clinical translation of EVs, standardized workflows and a deeper mechanistic understanding of EV function in the joint are essential. Identifying disease-specific EV biomarkers could enable earlier OA diagnosis and personalized treatment strategies, while optimizing therapeutic EVs could support regenerative approaches to slow or reverse joint degeneration and improve outcomes for human patients.

Osteoarthritis (OA) remains a major challenge for clinicians and researchers, as current treatments predominantly focus on symptomatic relief without completely addressing the underlying pathogenesis. In this regard, intraarticular injections of mesenchymal stem cells (MSCs) are emerging as a promising choice to mitigate pain and functional impairment in knee OA patients. The strong optimism for this therapeutic modality is based on experimental evidence supporting a role for MSCs in modulating inflammation, as well as encouraging clinical trials reporting safety and significant pain mitigation outcomes. However, inconsistencies related to their therapeutic efficacy remain a key concern. Therefore, a comprehensive understanding of the mechanisms by which MSCs exert their anti-inflammatory and joint-preserving effects is critically needed to ensure wider clinical translation. Recent research underscores the significance of MSCs as biomedicines with the potential to modulate the pro-inflammatory pathobiology of the entire OA joint. Their ability to crosstalk with joint resident cells and the infiltrating immune cells to reduce the overall catabolic load on the OA joints is being recognized as a primary mechanism underlying their therapeutic benefits. In this review, we discuss the significance of intraarticular MSC injections in the field of OA clinical research and focus on the immunomodulatory mechanisms underlying the ability of MSCs to modulate inflammation within OA joints by targeting both immune and resident joint cells. We identify current limitations and highlight the need for multidisciplinary clinical and basic science research to establish innovative approaches to further develop MSC-based therapies as efficacious biomedicines to treat OA patients.

Osteoarthritis (OA) is a multifactorial, mechano-inflammatory joint disorder characterized by cartilage degradation, synovial inflammation, and subchondral bone remodeling. Despite its high prevalence and significant impact on quality of life, no disease-modifying treatments have been approved. In many other disease areas, advanced omics technologies are impacting the development of advanced therapies. In OA, omics technologies such as genomics, transcriptomics, proteomics, and metabolomics have significantly increased our understanding of OA pathogenesis by uncovering molecular pathways driving disease progression. However, we have yet to see any tangible impact on the development of effective disease-modifying therapies. This review focuses on single- and multi-omics studies in OA, emphasizing their role in identifying molecular subtypes (endotypes) and therapeutic subtypes (theratypes). Multi-omics integration has revealed crosstalk between inflammatory, metabolic, and degradative processes, while spatial proteomics is beginning to provide insights into synovial tissue heterogeneity. However, challenges such as data complexity, lack of standardized frameworks, and limited translational validation hinder rapid progress. Future work will need to leverage artificial intelligence, single-cell, and spatial omics within longitudinal cohort studies. By addressing these challenges, omics-driven research holds promise for helping clinicians differentiating patients presenting with OA and psoriatic arthritis (PsA) affecting the hands or knees, developing personalized OA therapies, and achieving true disease modification beyond symptomatic relief.

Injury of the anterior cruciate ligament (ACL) is a common sports injury that can lead to post-traumatic osteoarthritis (PTOA) within 10-20 years. Surgical ACL reconstruction is often performed several weeks or months after injury, and this period between injury and ACL reconstruction may be a critical time for determining the risk of long-term PTOA progression. However, few (if any) studies in human patients have investigated the long-term effects of exercise or unloading between ACL injury and surgery. Early mobilization is often recommended to maintain range of motion and muscle strength, which are beneficial for positive outcomes of ACL reconstruction, but it is unknown what effects early mobilization or unloading have on long-term PTOA progression. In preclinical animal studies, a brief period of joint unloading immediately after ACL injury significantly decreased osteophyte formation and articular cartilage degeneration, while longer-term non-weightbearing caused muscle atrophy and articular cartilage degradation. Similarly, preclinical studies have shown that different intensities of exercise after knee injury can have divergent effects on PTOA development. Low intensity exercise was protective against joint degeneration, while higher intensity exercise accelerated PTOA progression. The beneficial or detrimental effects of exercise and unloading following ACL injury are likely dependent on the timing, duration, and intensity of these biomechanical interventions. This review summarizes the effects of these biomechanical interventions after ACL injury in both humans and animal models, with the goal of informing therapeutic and rehabilitation strategies for slowing or preventing PTOA progression after injury.

This review article examines the application of tissue engineering approaches in the treatment of osteoarthritis (OA), a complex joint disease characterized by tissue crosstalk and inflammation. The article covers preclinical testing platforms, including long-term in vitro studies, ex vivo models with osteochondral explants, and in vivo animal studies. It highlights the advantages and limitations of these models in evaluating tissue-engineered constructs for OA repair and focusses on cartilage specific treatments and resurfacing. The review also explores focal damage approaches such as autologous cultured chondrocytes and Autologous Matrix-Induced Chondrogenesis, which have shown improved patient outcomes. Additionally, it discusses natural and synthetic biomaterials used in cartilage repair, emphasizing the need for combining materials to enhance therapeutic efficacy. The importance of long-term studies in large animal models is underscored to develop effective strategies for cartilage repair. This minireview explores various approaches aimed at effectively addressing and repairing cartilage damage, covering preclinical testing platforms, cartilage resurfacing methods, and tissue engineering (TE) clinical trials. It also highlights challenges in developing future cartilage repair therapies.