Connective Tissue Research最新文献

Epigenetic mechanisms are implicated in osteoarthritis (OA) as they regulate the expression of several key genes involved in OA disease progression. This mini-review highlights major epigenetic studies in OA from the past 25 years, focusing on mechanistic and therapeutic perspectives. We discuss how DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) impact OA, highlighting preclinical studies targeting epigenetic mechanisms in mouse models. Indeed, existing studies demonstrate that DNA methylation regulates the expression of OA-related genes through DNA methyltransferases, and targeting their activity has shown promise in restoring cartilage homeostasis. EZH2 and DOT1L are key methyltransferases involved in histone methylation with opposing roles in OA: high EZH2 promotes disease progression and is a potential therapeutic target, whereas DOT1L exerts protective effects, partly by suppressing Wnt signaling. Additionally, targeting enzymes that catalyze histone acetylation (PCAF, BRD4) and deacetylation (HDAC1/2) has demonstrated therapeutic potential in preclinical OA models. ncRNAs-including miRNAs, circRNAs, and lncRNAs-regulate gene expression in OA tissues at multiple levels. Several miRNAs (e.g. miR-17, miR-27b-3p) influence cartilage homeostasis and OA pathogenesis, while circRNAs (e.g. circPDE4B) and lncRNAs (e.g. ELDR) have emerged as important disease regulators, offering new therapeutic avenues. Despite significant advancements in OA-related epigenetic mechanisms, clinical translation remains challenging due to the complexity of epigenetic regulation, patient heterogeneity, and limited success of preclinical studies. Importantly, epigenetic alterations are often context-specific, necessitating nuanced interpretation to accurately discern their role in OA. Future research should prioritize identifying specific epigenetic markers linked to clinical outcomes (e.g. structural changes, functional impairment, pain) and developing more selective and potent epigenetic modulators for therapeutic use.

Obesity is a major risk factor for osteoarthritis (OA), yet the precise contribution to the pathogenesis of OA is still not fully known. Although traditionally viewed as a weight-induced joint deterioration, recent studies have highlighted multiple mechanisms through which obesity contributes to OA. This review summarizes the advances in our understanding of the obesity-associated impact on OA and addresses the knowledge gaps within the field. It highlights the newest findings on the role of local and systemic factors produced by adipose tissue (AT). While AT-derived adipokines, such as leptin and resistin, have been shown to promote cartilage degradation by inducing pro-inflammatory cytokines through multiple pathways, others, like adiponectin, exert both pro- and anti-inflammatory effects. Furthermore, this review focuses on recent findings regarding the reorganization of the obesity-associated immune cell landscape during OA progression, highlighting the reduced content of synovial lining macrophages and patrolling monocytes, as well as the increased content of monocyte-derived macrophages, T cells, and myeloid suppressor cells in obese subjects. Additionally, this review explores the emerging link between the gut microbiome and metabolic dysfunction in obesity-related OA and examines the influence of sex differences on the disease. By framing OA as a systemic condition in the context of obesity, this review underscores the need for multifactorial therapeutic approaches and precision medicine strategies to address this growing public health challenge. By presenting current and emerging treatment strategies, this review features the multifaceted approach to managing and researching OA in obese populations, emphasizing the need for innovative preventative measures.

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.

Osteoarthritis (OA) is the most common musculoskeletal-related disease affecting over 27 million US adults, and no disease-modifying agents are currently available. Signs of bone remodeling are a major hallmark of OA, and include subchondral sclerosis (seen on x-ray), subchondral bone marrow lesions (seen on MRI), and osteophytosis. Recent work suggests subchondral bone remodeling is likely a driver of pain in OA. In this review, we seek to provide an overview on what is known about the cellular and molecular mechanisms that play a role in osteoarthritic subchondral bone remodeling and associated pain. Searching for "subchondral bone remodeling" "pain" and "osteoarthritis," we reviewed publications from 2015 onward. We found new details of how osteoblasts, osteoclasts, and osteocytes communicate in both autocrine and paracrine manners in OA, allowing identification of potential candidates that play a role in the aberrant bone remodeling seen in OA. Furthermore, there is new knowledge regarding mechanisms of how bone cells communicate with nociceptive neurons, providing potential candidates to target for treatment of OA pain. Recent clinical trials targeting OA-associated bone remodeling have been published with some encouraging results. In the future, more work is necessary to understand the inciting events that lead to the pathogenic cell behaviors, and unravel the complex cellular communication detailed in this review. In addition, efforts to understand the discordant results from recent trials of existing agents targeting bone remodeling and to develop novel bone-targeted agents for OA are needed.

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.

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.

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 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.