Connective Tissue Research最新文献

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.

Post-traumatic osteoarthritis (PTOA) is a common and debilitating problem following meniscal injury, which may lead to pain, loss of function, and early joint failure. Over the past 25 years, clinical, laboratory, and translational studies have greatly improved our understanding of PTOA pathogenesis and prevention. Clinical studies have established the benefit of meniscal preservation in preventing PTOA, leading to a significant increase in meniscus repair. Similarly, improved understanding of the biomechanical importance of the meniscal root attachment has increased focus on the detection and treatment of meniscal root injuries. Laboratory studies have demonstrated a preliminary mechanistic pathway of PTOA development following meniscal injury, whereby injury and altered joint loading stimulate a pro-inflammatory response that leads to both articular cartilage breakdown and impaired meniscal healing. In vitro evidence suggests that mechanical loading of the meniscus may ameliorate this catabolic response, with implications for treatment and rehabilitation protocols. Numerous animal models have emerged, allowing for in vivo assessment of PTOA initiation and offering a platform to test potential therapeutic targets. Despite these advances, meniscal repair remains imperfect and is not always possible, and investigations translating laboratory findings to the human setting have been limited. Future directions include further characterizing the immune and cellular responses to meniscal injury, investigating therapies to target the pro-inflammatory cascade and enhance meniscal healing, and developing new models to better distinguish PTOA pathogenesis in human subjects. Continued laboratory, translational, and clinical research efforts are required to identify treatment strategies to reduce the burden of PTOA after meniscal injury.

Progressive degradation of articular cartilage is characteristic of osteoarthritis (OA), but OA is more than a wear-and-tear disease of the cartilage. It is a complex, multifactorial disease affecting all joint tissues, amplified by local and systemic inflammation. Chondrocytes play a crucial role in cartilage homeostasis and various molecular pathways that leading to their catabolic state have been identified. Cartilage degradation fragments and direct exposure of chondrocytes to extracellular matrix molecules provide feedback loops that further stimulate the catabolic profile. Synovial inflammation and subchondral bone changes enhance cartilage degradation by changing the joint environment, secreting pro-inflammatory cytokines and proteolytic enzymes, and attracting immune cells. The heterogeneity of the disease is underscored by the recognition on various phenotypes and endotypes, although consensus on classification of subtypes is lacking. In the last 25 years, we have learned that timely treatment of joint injuries and repairing the meniscus are the best options to delay cartilage degradation and the development of post-traumatic OA. In addition, clinical studies have shown that cartilage thickness can be restored, but it does not necessarily provide clinical improvements. So far, there is no disease modifying OA drug (DMOAD) available. The development of DMOADs is partially hindered by the requirement of long preclinical and clinical studies, as cartilage degradation is a slow process. Availability of biomarkers as surrogate endpoint could accelerate the development. Biomarker panels for early diagnosis and patient stratification could also advance the field. Currently emerging treatment approaches, such as using regenerative medicine, promising for successful treatment.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown, chronic pain, and disability. Post-traumatic osteoarthritis (PTOA), a secondary form of OA, arises from joint injuries and consistently accounts for a proportion of symptomatic cases. Unlike primary OA, PTOA has a well-defined initiation point, presenting an opportunity for early intervention. Over the past two decades, research has shifted from a cartilage-centric view to a broader understanding of OA as a multifaceted disease involving inflammation, oxidative stress, and complex molecular crosstalk between chondrocytes, synoviocytes, osteocytes, and immune cells. Key inflammatory mediators, such as IL-1β, IL-6, TNF-α, and Wnt/β-catenin signaling, drive disease progression. Advances in imaging, biomarker discovery, and animal models have provided insights into early disease mechanisms. However, gaps remain in understanding the molecular events that trigger PTOA onset, the interplay between joint tissues, and the identification of reliable early biomarkers. Delayed diagnosis, lack of disease-modifying therapies, and OA's complexity remain critical barriers. Future directions should focus on precision medicine integrating biomarkers, imaging, and artificial intelligence for early diagnosis and risk stratification. Emerging regenerative and gene therapies, while promising, would benefit from moving beyond single-pathway targeting, as OA's multifaceted nature makes a combination approach desirable to simultaneously address inflammation, oxidative stress, cartilage matrix degradation, and tissue repair. Multidisciplinary collaborations between clinicians, molecular biologists, and bioengineers are essential to translating discoveries into effective interventions. A paradigm shift toward early, personalized treatment strategies is necessary to improve long-term outcomes in PTOA and OA management.

Clinically meaningful therapeutics targeting osteoarthritis pain have remained elusive over the years, but the collective understanding of mechanisms driving joint pain has continued to progress, offering a hopeful future. Recent significant discoveries in the field include detailed characterizations of structural and functional neuroplasticity within the joint, highlighting the contributions of non-neuronal cells in mediating this neuroplasticity. Notably, nerve growth factor has been identified as an important mediator of nociceptor sensitization and is expressed by many cells in the OA joint (e.g, chondrocytes, synovial fibroblasts, macrophages, osteoclasts). The release of pain-sensitizing mediators from non-neuronal cells is largely attributed to tissue damage and inflammation; however, the role of metabolism in OA pain development has begun to garner more attention and is discussed further in this narrative minireview. Altered whole-body and cellular metabolism can influence pain through various mechanisms, including adipokine hormonal signaling and metabolite production from catabolic pathways. The emerging potential of glucagon-like peptide-1 receptor agonists to treat osteoarthritis pain and possible mechanisms are discussed. Finally, the future of elucidating pain mechanisms and translational success will require novel experimental approaches and increased use of human tissue-based models, which are briefly discussed.

The primary function of our joints is to provide pain-free movement. However, with osteoarthritis (OA), the joint's structures are damaged, potentially leading to chronic joint pain. While it is logical to assume chronic OA pain relates to tissue destruction, a direct relationship between joint structure and pain is not the full story. For the last 25 years, epidemiologic data estimates that there are as many asymptomatic cases of OA as symptomatic cases in the United States. Thus, the relationship between OA pathology and painful symptoms is more complex than "more damage leads to more pain." This OA pain enigma is one of the outstanding challenges in the field. Since the ultimate function of the joint is to provide pain-free movement, this narrative review discusses our opinions on how biomechanics can continue to advance our understanding of joint function within the context of chronic OA pain. Using multiscale mechanics, we have learned critical lessons on how loads are transferred during movement. Tissue structure-function modeling has begun to reveal how articular cartilage produces its extraordinary mechanical functions. Moreover, biomechanics principles are being incorporated into rehabilitation and "prehabilitation" strategies in the clinic. Within these biomechanical lessons, a critical challenge remains for the OA joint-is our goal pain free movement or restoration of the joint? Within the OA pain enigma, the relationship between pain and function remains closely entwined, and our outlook sees a critical role for biomechanics research advancing our understanding of chronic OA pain.

Objective: Osteoarthritis (OA) is the most common musculoskeletal disorder, primarily affecting knee joints and causing pain and disability. The infrapatellar (IFP) and the suprapatellar (SFP) fat pad are knee adipose tissues that play essential mechanical roles during articular activity but are also sources of adipokines and cytokines, contributing to OA progression. For this reason, this work aims to provide new insights into IFP and SFP implications in knee OA.

Materials and methods: IFP and SFP tissue mechanical properties were studied through compression, indentation and shear mechanical tests performed on samples collected from patients who underwent total knee arthroplasty surgery due to end-stage OA. The energy loss, peak stress, and initial and final elastic moduli were calculated from the unconfined compression tests. The time-dependent response, evaluated in terms of equilibrium relative stiffness, was computed from stress-relaxation loading conditions. Considering shear tests, they provided strain-energy dissipation density, peak shear stress, and the shear moduli.

Results: Experimental results showed the typical adipose tissue mechanics features: non-linear stiffening with strain and time-dependent response. Experimental results showed that OA IFP is stiffer than OA SFP, indeed IFP final compression elastic modulus was greater than the SFP (84.43 kPa vs 35.54 kPa respectively) (p = 0.042). Regarding the viscoelastic properties they were comparable: the equilibrium relative stiffness was reported as 0.13 for IFP and 0.11 for SFP (p = 0.026).

Conclusions: These outcomes provide new insights into the OA influence on knee mechanics and lay the basis for developing computational tools to improve knee prosthesis design.

Background: Chondrocytes, the only native cell type in cartilage, use mechanosensitive ion channels such as Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 to transduce mechanical forces into transcriptomic changes that regulate cell behavior under both physiologic and pathologic conditions. Recent work has identified and characterized the differentially expressed genes (DEGs) that are upregulated following TRPV4 or PIEZO1 activation, but the transcriptomic systems downregulated by these ion channels also represent an important aspect of the chondrocyte regulatory process that remains poorly studied.

Methods: Here, we utilized previously established bulk RNAsequencing libraries to analyze the transcriptomes downregulated by activation of TRPV4 and PIEZO1 through differential gene expression analysis (using DESeq2), Gene Ontology, RT-qPCR, and Weighted Gene Correlation Network Analysis (WGCNA).

Results: TRPV4 and PIEZO1 activations downregulated largely unique sets of DEGs, though the set of DEGs downregulated by TRPV4 exhibited a notable overlap with genes downregulated by treatment with inflammatory mediator Interleukin-1 (IL-1). The DEG set downregulated by PIEZO1 activation included genes associated with the G2/M cell cycle checkpoint, a system that checks cells for DNA damage prior to entry into mitosis, and this result was confirmed with RT-qPCR. WGCNA revealed modules of gene regulation negatively correlated with TRPV4, PIEZO1, and IL-1, outlining how these downregulated DEGs may interact to form gene regulatory networks (GRNs).

Conclusion: This study complements previous work in describing the full mechanosensitive transcriptome (or "mechanome") of differential gene expression in response to activation of mechanosensitive ion channels TRPV4 and PIEZO1 Q2 and suggests potential avenues for future therapeutic treatment design.