Physicochemical and biomechanical stimuli in cell-based articular cartilage repair

Articular cartilage is a unique load-bearing connective tissue with a low intrinsic capacity for repair and regeneration. Its avascularity makes it relatively hypoxic and its unique extracellular matrix is enriched with cations, which increases the interstitial fluid osmolarity. Several physicochemical and biomechanical stimuli are reported to influence chondrocyte metabolism and may be utilized for regenerative medical approaches. In this review article, we summarize the most relevant stimuli and describe how ion channels may contribute to cartilage homeostasis, with special emphasis on intracellular signaling pathways. We specifically focus on the role of calcium signaling as an essential mechanotransduction component and highlight the role of phosphatase signaling in this context

Adipose, Bone Marrow and Synovial Joint-Derived Mesenchymal Stem Cells for Cartilage Repair

Current cell-based repair strategies have proven unsuccessful for treating cartilage defects and osteoarthritic lesions, consequently advances in innovative therapeutics are required and mesenchymal stem cell-based (MSC) therapies are an expanding area of investigation. MSCs are capable of differentiating into multiple cell lineages and exerting paracrine effects. Due to their easy isolation, expansion, and low immunogenicity, MSCs are an attractive option for regenerative medicine for joint repair. Recent studies have identified several MSC tissue reservoirs including in adipose tissue, bone marrow, cartilage, periosteum, and muscle. MSCs isolated from these discrete tissue niches exhibit distinct biological activities, and have enhanced regenerative potentials for different tissue types. Each MSC type has advantages and disadvantages for cartilage repair and their use in a clinical setting is a balance between expediency and effectiveness. In this review we explore the challenges associated with cartilage repair and regeneration using MSC-based cell therapies and provide an overview of phenotype, biological activities, and functional properties for each MSC population. This paper also specifically explores the therapeutic potential of each type of MSC, particularly focusing on which cells are capable of producing stratified hyaline-like articular cartilage regeneration. Finally we highlight areas for future investigation. Given that patients present with a variety of problems it is unlikely that cartilage regeneration will be a simple “one size fits all,” but more likely an array of solutions that need to be applied systematically to achieve regeneration of a biomechanically competent repair tissue

Applying Proteomics to Study Crosstalk at the Cartilage-Subchondral Bone Interface in Osteoarthritis: current Status and Future Directions

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Clusterin secretion is attenuated by the proinflammatory cytokines interleukin‐1β and tumor necrosis factor‐α in models of cartilage degradation

The protein clusterin has been implicated in the molecular alterations that occur in articular cartilage during osteoarthritis (OA). Clusterin exists in two isoforms with opposing functions, and their roles in cartilage have not been explored. The secreted form of clusterin (sCLU) is a cytoprotective extracellular chaperone that prevents protein aggregation, enhances cell proliferation and promotes viability, whereas nuclear clusterin acts as a pro-death signal. Therefore, these two clusterin isoforms may be putative molecular markers of repair and catabolic responses in cartilage and the ratio between them may be important. In this study, we focused on sCLU and used established, pathophysiologically relevant, in vitro models to understand its role in cytokine-stimulated cartilage degradation. The secretome of equine cartilage explants, osteochondral biopsies and isolated unpassaged chondrocytes was analyzed by western blotting for released sCLU, cartilage oligomeric protein (COMP) and matrix metalloproteinases (MMP) 3 and 13, following treatment with the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α. Release of sulfated glycosaminoglycans (sGAG) was determined using the dimethylmethylene blue assay. Clusterin messenger RNA (mRNA) expression was quantified by quantitative real-time polymerase chain reaction. MMP-3, MMP-13, COMP, and sGAG release from explants and osteochondral biopsies was elevated with cytokine treatment, confirming cartilage degradation in these models. sCLU release was attenuated with cytokine treatment in all models, potentially limiting its cytoprotective function. Clusterin mRNA expression was down-regulated 7-days post cytokine stimulation. These observations implicate sCLU in catabolic responses of chondrocytes, but further studies are required to evaluate its role in OA and its potential as an investigative biomarker

Pristine carbon nanotube scaffolds for the growth of chondrocytes

The effective growth of chondrocytes and the formation of cartilage is demonstrated on scaffolds of aligned carbon nanotubes; as two dimensional sheets and on three dimensional textiles. Raman spectroscopy is used to confirm the presence of chondroitin sulfate, which is critical in light of the unreliability of traditional dye based assays for carbon nanomaterial substrates. The textile exhibits a very high affinity for chondrocyte growth and could present a route to implantable, flexible cartilage scaffolds with tuneable mechanical properties