Connective Tissue Research最新文献

Osteoarthritis (OA), long regarded as simply a disease of articular cartilage degeneration, has increasingly been recognized as a complex disorder involving multiple joint tissues, including the synovium. This review explores the emerging evidence that synovial changes seen in OA are not merely secondary to cartilage breakdown but may actively drive OA progression. We detail the physiological role of the synovium in joint homeostasis and highlight pathological remodeling processes, such as synovial hyperplasia, immune cell infiltration, and fibroblast activation, that contribute to joint degeneration. Mechanistic insights implicate fibroblast-like synoviocytes and synovial macrophages in initiating and perpetuating inflammatory and catabolic cascades that alter synovial fluid composition, impair cartilage integrity, and exacerbate disease symptoms. Clinical and preclinical data increasingly link synovitis and synovial damage to structural disease progression and pain, underscoring their prognostic and therapeutic significance. Despite promising targets, effective disease-modifying therapies remain elusive due to the molecular complexity and clinical heterogeneity of the disease and limitations in early diagnostic evaluations. To overcome this, innovative research methods, improved diagnostic tools, and interdisciplinary collaboration will be critical. Collectively, this work advocates for a paradigm shift that the synovium is a central player in OA pathogenesis and a viable target for therapeutic intervention.

Synovial joints are complex multi-tissue organs that permit movement. A well-functioning synovial joint relies on complex interconnected homeostatic mechanisms to maintain joint organ function in response to biomechanical and metabolic demands. These homeostatic mechanisms include, but are not limited to, appropriate mechanobiological responses to load, nutrient delivery from its vasculature, lubrication, proprioception and pain, immunosurveillance, and maintenance of the extracellular matrix (ECM) composition. In osteoarthritis (OA), joint homeostasis is chronically deranged leading to failure of the synovial joint organ and impairment or loss of function. Maintaining synovial joint organ homeostasis is therefore critical to joint function and relies on complex interconnected physiological process at the joint level. As OA prevalence continues to rise, deepening our understanding of the integrated systems that sustain joint homeostasis may identify fruitful avenues for therapeutic intervention. However, key knowledge gaps will need to be addressed including, characterizing vessel function in joint diseases, understanding the role of novel proteases in ECM catabolism, and determining the role of non-macrophage synovial immune cells in joint immunosurveillance. We believe that future research will find greater success if these homeostatic mechanisms are viewed as a single integrated system that considers the crosstalk between mechanical, vascular, immune, and biochemical factors. Therefore, in this review, we explore the interconnected mechanisms that support joint homeostasis and how dysregulation can lead to failure of the synovial joint organ.

Oxygen availability plays a critical role in maintaining cartilage homeostasis and influencing the progression of osteoarthritis (OA). Articular cartilage is an avascular tissue that depends on a tightly regulated hypoxic microenvironment, with oxygen gradients shaped by diffusion from synovial fluid, cartilage thickness, and mechanical loading. Both degenerative OA, which develops gradually with age, and post-traumatic osteoarthritis (PTOA), which follows joint injury and progresses more rapidly, may involve disruption of this oxygen balance. Such dysregulation, whether through reduced or elevated oxygen tension, can impair chondrocyte metabolism, increase reactive oxygen species (ROS) production, and alter hypoxia-inducible factor 1-alpha (HIF-1α) signaling, ultimately contributing to cartilage degeneration. This mini-review explores the complex oxygen dynamics in cartilage and their potential role in OA. We highlight current knowledge gaps in oxygen level assessment and mechanistic understanding, and discuss emerging therapeutic and biomaterial-based strategies, including oxygen-sensing nanoparticles, ROS-responsive scaffolds, and oxygen-generating materials, that aim to modulate the joint oxygen environment. These approaches underscore the need for temporally controlled oxygen-related pathway modulation to support cartilage repair. Advancing our understanding of oxygen regulation in joint tissues may offer new opportunities for more effective, stage-specific OA therapies.

Osteoarthritis (OA) is one of the most common health conditions worldwide leading to immense individual and societal burden. Current treatments for OA are inadequate with no approved structural disease modifying therapies, and existing options for chronic pain only moderately successful long-term. Improving this bleak picture requires a better understanding of OA molecular pathophysiology, how this differs between individuals and over time. Critical in this goal are animal models. There have been four key advancements in this field that have dramatically improved OA pathophysiology discovery research: (1) initial studies showing mouse OA-risk is modified by the same factors as humans-age, sex/sex-hormones, diet and genetics (1952-65); (2) first studies of naturally-occurring OA in mice with spontaneous (1972-81) and induced (1993) genetic mutations (GMs); (3) developing reproducible inducible models with good structural and symptomatic fidelity to human OA (1990-2005); and (4) using inducible and spontaneous OA-models in GM-mice to show disease and symptom modification and define molecular causality (1999-present). These milestones revolutionized OA pathophysiology research, such that there are now >500 unique genes/gene-products identified as having significant effects on OA (beneficial or detrimental). Studies in different mouse OA-models have underpinned the concept of OA-phenotypes, and more particularly endotypes and theratypes, with ~35% of tested molecular targets having different effects on post-traumatic (pt)OA versus spontaneous/age-associated-OA. Deciphering and translating the enormous and growing data from animal-models into effective therapeutics for people remains challenging. This will require better identification and stratification of patients with different OA pheno/endotypes, and improved collaboration between clinical and pre-clinical researchers.

Osteoarthritis (OA) is a leading cause of pain and disability globally,characterized by progressive cartilage degeneration, subchondralbone remodeling, and synovial inflammation. Current treatmentsprimarily offer symptomatic relief without addressing the underlyingdisease mechanisms or halting progression. Gene therapy hasemerged as a promising strategy to target the molecular drivers ofOA by modulating key pathways involved in inflammation, tissuedegeneration, and pain. This review summarizes recent advancesin OA gene therapy, including anti-inflammatory approachestargeting IL-1β and IL-10, as well as regenerative strategiesleveraging TGF-β1 and FGF-18. Preclinical and early clinicalstudies have shown encouraging results in both symptom reliefand cartilage preservation. However, significant challengesremain, including vector safety, immune responses, and thecomplex, heterogeneous nature of OA that complicates treatmentresponse. The integration of precision medicine with improved genedelivery platforms and combinatorial therapeutic strategies holdsstrong potential to overcome these limitations. Collectively, theseinnovations may accelerate the development of disease-modifyingosteoarthritis drugs (DMOADs) and provide long-term, effectivetherapeutic options for patients.

Osteoarthritis (OA) is a leading cause of disability worldwide, significantly impacting patient mobility and quality of life. Its increasing prevalence presents a growing socioeconomic burden. Despite extensive research, no FDA-approved disease-modifying osteoarthritis drugs (DMOADs) exist, leaving patients reliant on symptomatic treatments like NSAIDs, corticosteroids, and joint replacement surgeries. A major challenge in OA drug development is the heterogeneity of the disease. Traditional approaches that target single molecular pathways often fail to address the multifactorial nature of OA. Given the high failure rate and costs of novel drug development, drug repurposing has emerged as a promising alternative. Several repurposed drugs, predominantly those affecting inflammation (e.g. Methotrexate, Adalimumab), metabolism (e.g. Metformin, Liraglutide) and bone homeostasis (e.g. Risedronate, Clodronate) have been investigated for OA. However, inconsistent clinical trial results underscore the need for improved screening, patient stratification, and mechanistic understanding. Recent insights into OA pathophysiology, such as the role of cellular senescence, mitochondrial dysfunction, and translational alterations, highlight novel targets for repurposing efforts. The future of OA drug repurposing will likely be shaped by advancements in high-throughput screening, artificial intelligence-driven drug discovery, and strategies that align treatments with patient-specific disease mechanisms. By integrating these innovations, drug repurposing holds potential to deliver DMOADs and improve patient outcomes worldwide.

Osteoarthritis (OA) is a complex, multifactorial joint disease and a leading contributor to global disability. Despite its high prevalence and socioeconomic burden, no curative or preventive therapies currently exist. The ability to detect early OA, or even "pre-OA" could provide the opportunity for earlier interventions. Current conventional imaging modalities such as radiography and Magnetic resonance imaging (MRI) are limited by their inability to detect early pathophysiological molecular changes. This review highlights the potential of positron emission tomography (PET) imaging to transform the diagnosis and therapeutic monitoring of OA. PET has emerged as a transformative tool capable of visualizing early metabolic, inflammatory, and cellular alterations. But while current clinical PET imaging with [¹⁸F]Fluorodeoxyglucose ([¹⁸F]-FDG) and [¹⁸F] Sodium fluoride ([¹⁸F]-NaF) can assess synovial inflammation and subchondral bone remodeling, their lack of specificity hinders further advances. We also review the recent development of radiotracers targeting specific immune and mesenchymal cell populations, such as translocator protein (TSPO) and fibroblast activation protein inhibitor (FAPI) that have demonstrated potential for characterizing the inflammatory endotype in OA and monitoring treatment response. Given the lack of validated cell-specific tracers, limited studies in early-stage or asymptomatic OA, and few longitudinal data sets, future research should prioritize development and validation of pathophysiology-specific tracers and incorporation of PET into longitudinal and interventional studies. This evolving field holds promise not only for advancing OA preclinical research but also for informing precision diagnostics and early therapeutic strategies in clinical practice.

Osteoarthritis is a whole-joint disease. While some intra-articular tissues are in physical contact with each other, it is the synovial fluid that acts as a major connecting medium into which joint tissues and cells release their bioactive molecular content. Osteoarthritic synovial fluid contains a plethora of systemic and locally derived biomolecular factors, including cells, extracellular vesicles, proteins, crystals, metabolites, and RNAs. While many of these biomolecular factors are primarily considered as potential biomarkers for OA diagnostics, the bioactivity relayed by these factors and their critical contributions to osteoarthritis pathobiology have received less attention. In this review, we highlight insights into the bioactivity of molecular constituents contained within human osteoarthritic synovial fluid, its intrinsic bioactivity, as well as its potential, and the barriers to use synovial fluid to biomolecularly stratify individuals for specific targeted therapies or osteoarthritis stage.

Osteoarthritis (OA) is a multifactorial joint disease characterized by progressive cartilage degradation, synovial inflammation, and subchondral bone remodeling. Despite its significant global health burden, there are currently no disease-modifying pharmacological therapies for OA. Gene therapy, leveraging viral and non-viral vectors to deliver therapeutic transgenes into the joint environment, shows significant promise. This mini-review highlights recent innovations in OA gene therapy pipelines, focusing on Platforms employing recombinant adenovirus, adeno-associated virus (AAV), and herpes simplex virus vectors. Strategies include AAV-mediated delivery of interleukin-1 receptor antagonist (IL-1Ra) and truncated nkx3.2 transcription factor to modulate inflammation and promote chondrocyte survival. Non-viral approaches, such as plasmid DNA encoding interleukin-10, are also under investigation. Emerging data from preclinical and clinical studies demonstrate the feasibility of achieving sustained, intra-articular transgene expression with therapeutic efficacy in animal models and early-phase human trials. However, challenges persist, including immune barriers to repeat dosing, variability in vector performance, and the high costs of treatment. Additionally, agerelated declines in transduction efficiency, the heterogeneity of OA, and systemic metabolic influences complicate therapeutic outcomes. To overcome current regulatory obstacles, future research must prioritize the refinement of vector systems to enhance safety, potency, and specificity, as well as the development of combination therapies integrating genetic and conventional approaches, targeting pain and improving function. Gene therapy has transformative potential for improving OA management and an important priority is multidisciplinary collaboration to translate preclinical innovations into accessible, effective treatments for a highly heterogeneous and aging patient population.

Osteoarthritis (OA) is a debilitating degenerative disease of the joints and one of the most prevalent joint disorders affecting millions of individuals worldwide. This disease is highlighted by significant morbidity owing to encumbering joint pain and functional impairment. OA ensues following disruption of normal homeostasis in the joint resulting from aging, metabolic changes, or as a consequence of joint injury (referred to as post-traumatic OA). These processes are largely driven by low-grade inflammation that gradually compromises the anabolic and protective activities of joint resident cells including chondrocytes, synovial fibroblasts (SFs) and immune cells. Ample research suggests that the process of cartilage deterioration is the endpoint of complex pathologic processes culminating with synovitis, subchondral bone sclerosis, osteophyte formation, aberrant remodeling, and ultimately articular cartilage degradation. There remains a great need for identifying early markers and a "window of opportunity" to enable timely interventions in OA. However, this effort is hampered by the complex nature of the disease and its comorbidities. Joint holistic approaches using recent unbiased multi-omic tools are currently at the forefront promising better understanding of OA development. Currently, there are no meaningful disease-modifying drugs to treat OA, with surgical procedures as the ultimate effective intervention for end stage OA patients. The disability, pain, and surgical costs associated with OA management position this disease among the costliest and onerous for our society. This mini review will highlight advances in the last two decades and major obstacles limiting progress in OA research with particular emphasis on metabolic and inflammatory comorbidities.