Abstract
Osteoarthritis is a degenerative joint disease of the articular cartilage characterized by the loss of cartilage, limited range of motion, joint pain and tenderness, and limited physical movements. An imbalance between regenerative and degenerative factors results in increased loss of cartilage leading to osteoarthritis. Osteoarthritis is not only a disease of cartilage but involves the whole joint including tendon, ligament, meniscus, muscle, and synovial membrane. The weakness of the quadriceps muscles and inflammation of the articular structures of the joint enhance the progression of cartilage degeneration and loss. The weakness of the muscles may be due to vitamin D deficiency, which in turn is associated with chronic inflammation and an increased prevalence and incidence of osteoarthritis. The initial damage caused by mechanical or shear stress, trauma or injury, or an improper gait results in the secretion of damage associated molecular patterns (DAMPs) including high mobility group box-1 (HMGB-1), receptor for advanced glycation end products (RAGE), and alarmins (S100A8 and S100A9). Aging can also result in physiological accumulation of advanced glycation end products (AGEs). These DAMPs instigate a cascade of inflammatory responses and increase the secretion of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, and anti-inflammatory cytokines IL-10 and IL-37. Increased secretion of these pro-inflammatory cytokines results in the recruitment of inflammatory cells such as monocytes and macrophages. The activation of various inflammatory and pro-damage mediators including triggering receptor expressed on myeloid cells (TREMs), toll like receptors (TLRs), cytoplasmic kinases, transcriptional factors, and matrix metalloproteinases (MMPs). The role of these pro-inflammatory cytokines and inflammatory and pro-damage mediators in the pathogenesis of rheumatoid arthritis, synovitis, and osteoarthritis has been well described. The role of newly discovered cytokines of IL-1 family, IL-33 and IL-37, in the pathogenesis of rheumatoid arthritis and synovitis has been reported in the literature. However, their role in relation to osteoarthritis is yet to be established. Increased secretion of DAMPs is associated with an increased production of pro-inflammatory cytokine IL-33, whereas the increase in inflammation results in the secretion of anti-inflammatory cytokine IL-37 as a compensatory mechanism. Since vitamin D deficiency is associated with chronic inflammation and osteoarthritis, and vitamin D regulates the secretion of IL-33 and IL-37; one may speculate that vitamin D could also play a crucial role in the pathogenesis of osteoarthritis and may affect IL-33 and IL-37 effects on mediators of inflammation within the joint. IL-33, IL-37, and vitamin D play a crucial role in macrophage differentiation and polarization, the main effectors of chronic inflammation within the joint. Taken together, it is logical to infer that IL-33, IL-37, and vitamin D interactions may have an immunomodulatory effect on the expression levels and action of various pro-inflammatory and pro-damage mediators. However, the immunomodulatory role of IL-33, IL-37, and vitamin D in OA has not been reported in the literature. In this study, for the first time, the interactive and counteractive role of IL-33, IL-37, and vitamin D on TREM-1, TREM-2, TLR-2, TLR-4, NF-κB, RAGE, HMGB-1, MMP-2, MMP-9, and macrophage polarization has been elucidated using normal and osteoarthritic human chondrocytes and the expression levels of these have been analyzed in osteoarthritic human knee and hip cartilage, and vitamin D deficient, vitamin D sufficient, and vitamin D supplemented hyperlipidemic microswine.