Role of NFAT1 transcription factor in maintaining metabolic homeostasis and structure of synovial joints and intervertebral discs

Abstract

Purpose: Osteoarthritis (OA) and intervertebral disc degeneration are common diseases in middle-aged and older individuals. No pharmacologic therapy is currently available to halt or reverse the progression of these disorders, largely because their pathogenesis remains unclear. Previous studies suggest that overexpression of catabolic proteinases and inflammatory cytokines may contribute to the development of OA and intervertebral disc degeneration. However, the roles of specific transcription factors in maintaining metabolic homeostasis and tissue structure of synovial joints and intervertebral discs are not fully understood. This study aimed to examine the role of NFAT1 transcription factor in maintaining metabolic homeostasis and tissue structure of major synovial joints and intervertebral discs in mice. Methods: The hip, knee, shoulder, and spine (L4-S1) tissue samples of Nfat1 knockout (Nfat1-/-) and wild-type mice were harvested at 2, 4, 6, and 12 months of age for radiographic, histopathological, and immunohistochemical analyses. Total RNA was isolated from articular cartilage and L1-3 intervertebral discs for gene expression analyses. Results: Nfat1-/- mice began to show OA-like cartilage degradation in major synovial joints (hip, knee, and shoulder) at the young adult stage, followed by synovial hypertrophy, chondro-osteophyte formation, and alteration of subchondral bone. Overexpression of catabolic proteinases and proinflammatory cytokines with decreased expression of anabolic chondrocyte markers was observed in articular cartilage and intervertebral discs of adult Nfat1-/- mice. However, the abnormality of their expression is more severe in articular cartilage than in intervertebral discs. Furthermore, structural changes in the discs, vertebral endplates, and vertebral bodies of Nfat1-/- mice were not apparent by 12 months of age. Conclusions: NFAT1 plays a key role in regulating the metabolic homeostasis in both articular cartilage and intervertebral discs of mice. NFAT1 deficiency causes severe OA-like structural changes in articular cartilage and periarticular tissues, but not in intervertebral discs or vertebral bodies. These findings suggest that synovial response and mechanical factors may be involved in the development of NFAT1 deficiency-induced OA in load-bearing synovial joints.