Regulatory role of NFAT1 signaling in articular chondrocyteactivities and osteoarthritis pathogenesis

Osteoarthritis (OA), the most common form of joint disease, is characterized clinically by joint pain, stiffness,and deformity. OA is now considered a whole joint disease;however, the breakdown of the articular cartilage remains themajor hallmark of the disease. Current treatments targeting OA symptoms have a limited impact on impeding orreversing the OA progression. Understanding the molecular and cellular mechanisms underlying OA development isa critical barrier to progress in OA therapy. Recent studies by the current authors’ group and others have revealedthat the nuclear factor of activated T cell 1 (NFAT1), a member of the NFAT family of transcription factors, regulatesthe expression of many anabolic and catabolic genes in articular chondrocytes of adult mice. Mice lacking NFAT1exhibit normal skeletal development but display OA in both appendicular and spinal facet joints as adults. Thisreview mainly focuses on the recent advances in the regulatory role of NFAT1 transcription factor in the activities ofarticular chondrocytes and its implication in the pathogenesis of OA.

Genetic factors in intervertebral disc degeneration

Low back pain(LBP)is a major cause of disability and imposes huge economic burdens on human society worldwide.Among many factors responsible for LBP,intervertebral disc degeneration(IDD)is the most common disorder and is a target for intervention.The etiology of IDD is complex and its mechanism is still not completely understood.Many factors such as aging,spine deformities and diseases,spine injuries,and genetic factors are involved in the pathogenesis of IDD.In this review,we will focus on the recent advances in studies on the most promising and extensively examined genetic factors associated with IDD in humans.A number of genetic defects have been correlated with structural and functional changes within the intervertebral disc(IVD),which may compromise the disc’s mechanical properties and metabolic activities.These genetic and proteomic studies have begun to shed light on the molecular basis of IDD,suggesting that genetic factors are important contributors to the onset and progression of IDD.By continuing to improve our understanding of the molecular mechanisms of IDD,specific early diagnosis and more effective treatments for this disabling disease will be possible in the future.

Epigenetic regulation of gene expression in osteoarthritis

Osteoarthritis(OA)is the most common form of joint disease and the leading cause of chronic disability in middle-aged and older populations.The development of diseasemodifying therapy for OA currently faces major obstacles largely because the regulatory mechanisms for the function of joint tissue cells remain unclear.Previous studies have found that the alterations in gene expression of specific transcription factors(TFs),pro-or antiinflammatory cytokines,matrix proteinases and extracellular matrix(ECM)proteins in articular cartilage may be involved in the development of OA.However,the regulatory mechanisms for the expression of those genes in OA chondrocytes are largely unknown.The recent advances in epigenetic studies have shed light on the importance of epigenetic regulation of gene expression in the development of OA.In this review,we summarize and discuss the recent studies on the regulatory roles of various epigenetic mechanisms in the expression of genes for specific TFs,cytokines,ECM proteins and matrix proteinases,as well the significance of these epigenetic mechanisms in the pathogenesis of OA.