Connective Tissue Research最新文献

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.

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.

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.

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.

Osteoarthritis (OA) is a multifactorial joint disease characterized by cartilage degradation, subchondral bone remodeling, synovitis, and cartilage matrix degradation. The synovial membrane plays a pivotal role in the progression of OA through low-grade inflammation and secretion of catabolic enzymes under altered mechanical homeostasis. While widely used to study OA pathogenesis and therapies, in vitro models (e.g. 2D synoviocyte co-cultures) frequently lack critical aspects of the in vivo synovial microenvironment, such as cellular heterogeneity, physiologically relevant mechanical stress, and dynamic cell-matrix crosstalk. These shortcomings reduce their translational value. This translational gap indicates the need for advanced 3D microengineered platforms that integrate patient-specific cells, biomechanical elements, and real-time biosensing to bridge in vitro findings to clinical outcomes. Recent advances in microengineering offer innovative in vitro systems such as OA synovium-on-a-chip, 3D-printed constructs, and hydrogel-based organoids that recapitulate key features of the synovial microenvironment. These tools enable precise control over mechanical stimuli, matrix composition, and cell-cell signaling. This review summarizes the microenvironment of the OA synovium, critiques existing model systems, and highlights emerging microengineering strategies aimed at better mimicking OA pathophysiology and advancing translational research.

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.

Exercise-induced inflammation and free radical production are crucial for recovery, yet excess inflammation poses risks to equine athletes, leading to conditions like arthritis. Spirulina, recognized for its antioxidant and anti-inflammatory properties, could mitigate degenerative diseases without hindering post-exercise recovery. This study investigates Spirulina's direct impact on cartilage responses to LPS-induced inflammation in normoxic and hypoxic conditions, focusing on outcomes relevant to cartilage matrix turnover and exercise-induced inflammation. Spirulina underwent simulated digestion and liver metabolism, yielding a simulated biological extract (SP_sim). In the normoxic experiment, porcine cartilage explants were cultured with SP_sim (0, 30, or 90 μg/mL) for 72 h after 24 h in basal media, with LPS (0 or 10 μg/mL) added for the final 48 h. The hypoxic experiment mirrored this, with explants transferred to a hypoxia chamber for the final 48 h. Media samples collected at 0, 24, and 48 h were analyzed for biomarkers related to cartilage turnover (GAG), and exercise-induced inflammation (IL-6 and NO). Cell viability, assessed by live:dead staining, remained > 97% and unaffected by oxygen tension. In normoxic conditions, SP_sim (30 μg/mL) significantly reduced GAG release at 48 h. Under hypoxia, SP_sim (30 and 90 μg/mL) inhibited LPS-induced GAG release. SP_sim (90 μg/mL) increased IL-6 and NO production in LPS-stimulated explants in normoxia, and a similar effect was observed with the lower SP_sim dose (30 μg/mL) in hypoxic conditions. These results suggest that Spirulina may enhance cartilage mediators, potentially promoting healthy cartilage turnover during exercise recovery.

Purpose: This review highlights the transformative impact of spatial transcriptomics on orthopedic research, focusing on its application in deciphering intricate gene expression patterns within musculoskeletal tissues.

Methods: The paper reviews literature for spatial transcriptomic methods, specifically 10X Visium, 10X Xenium, seqFISH+, MERFISH, NanoString GeoMx DSP, used on musculoskeletal tissues (cartilage, joints, bone, tendon, ligament, and synovium).

Results: Searches identified 29 published manuscripts reporting spatial transcriptomic data in cartilage, bone, tendon, synovium, and intervertebral disc. Most publications of spatial transcriptomic data are from tendon and synovium. 10X Visium has been used in 22 of the 29 papers identified. Spatial transcriptomics has been used to identify novel cell populations and cell signaling pathways that regulate development and disease.

Conclusions: Imaging-based spatial transcriptomic methods may be better for hypothesis testing as they generally have subcellular resolution but sequence fewer genes. Sequencing methods may be better for untargeted, shotgun approaches that can generate useful hypotheses from the spatial data from unimpaired tissue sections. Spatial transcriptomic methods could become useful for clinical diagnostics and precision medicine approaches.