Role of suppressors of cytokine signaling 3 in bone inflammatory responses

Abstract

Suppressor of cytokine signaling 3 (SOCS3) is a potent regulator of cytokine signaling in macrophages and T cells. In recent studies, evidence has been provided for SOCS3 activation in all major bone cells including osteoclasts, chondrocytes, synoviocytes, and osteoblasts. The investigation of SOCS3 function in bone remodeling systems implicates SOCS3 as a key signaling molecule in bone cell-mediated inflammatory responses. Both pro- and anti-inflammatory functions of SOCS3 have been demonstrated in different types of bone cells. This review provides an overview of the important role of SOCS3 in inflammatory responses of various bone cells and in bone inflammatory disorders such as periodontal disease and arthritis. Understanding the roles of SOCS3 in inflammatory diseases of bone and joints such as arthritis, osteomyelitis, and periodontal diseases is critical to revealing insights into signaling pathways that can be manipulated in potential therapeutic approaches.

Keywords: SOCS3; bone; inflammation.

Figure 1

The complex role of SOCS3 in bone cells. SOCS3 is expressed in osteoblasts, osteoclasts, chondrocytes, and synoviocytes. In osteoblasts, SOCS3 inhibits E. coli LPS-induced IL-6 and MMP-13 expression by suppressing CCAAT/enhancer-binding protein β activity. In contrast, SOCS3 positively regulate osteoclastogenesis by blocking the inhibitory effect of inflammatory cytokines on receptor activator of the NF-kappaB ligand-mediated osteoclast differentiation signals. SOCS3 deficiency in the hematopoietic and endothelial cell compartment results in osteoclast generation and bone destruction. In chondrocytes, SOCS3 inhibits the Stat3-mediated inflammatory pathway. In contrast, there is an increased expression of SOCS3 in human arthritic chondrocytes compared with control chondrocytes. There is a strong positive correlation between SOCS3 expression and MMP-13 suppression. Tacrolimus, an immunosuppressant, was shown to exhibit anti-arthritic effects by regulating inflammatory cytokine production in RA. Additionally, tacrolimus prevents differentiation of cells into mature osteoclasts, thereby conferring protection against bone resorption. In fibroblast-like synoviocytes, tacrolimus increases SOCS3 protein expression while it decreases receptor activator of NF-κB ligand (RANKL) expression as well as JAK2 and STAT3 phosphorylation.