Modulatory Effect of 1,25-Dihydroxyvitamin D₃on IL1β-Induced RANKL, OPG, TNFα, and IL-6 Expression in Human Rheumatoid Synoviocyte MH7A

Abstract

Receptor activator of nuclear factor κB ligand (RANKL) plays a crucial role in the bone erosion of rheumatoid arthritis (RA) by prompting osteoclastogenesis. Considering that 1,25(OH)2D3 has been suggested as a potent inducer of RANKL expression, it should clarify whether vitamin D supplement could result in RANKL overexpression and thereby facilitate excessive osteoclastogenesis and bone resorption in RA. Here, we investigated modulatory effect of 1,25(OH)2D3 on the expression of RANKL and its decoy receptor osteoprotegerin (OPG) in an inflammatory condition of human rheumatoid synoviocyte MH7A. MH7A cells were stimulated with IL1β and then treated with different concentrations of 1,25(OH)2D3 for 48 h. A significantly elevated OPG/RANKL ratio and markedly decreased levels of IL-6 and TNFβ mRNA expression in cells and IL-6 protein in supernatants were observed in IL1β-induced MH7A in the presence of 1,25(OH)2D3 compared with those in the absence of it. Osteoclast formation was obviously decreased when RAW264.7 cells were treated with both 1,25(OH)2D3 and IL1β. In summary, although it has a biological function to induce RANKL expression, 1,25(OH)2D3 could upregulate OPG/RANKL ratio and mediate anti-inflammatory action in an inflammatory milieu of synoviocyte, contributing to the inhibition of inflammation-induced osteoclastogenesis in RA.

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

“…The binding capacity of OPG to RANKL is higher than that of RANK to RANKL, which competitively binds RANKL, thereby competitively inhibiting its binding to RANK (39). Consequently, OPG may inhibit the differentiation of osteoclasts (39). The present results suggested that LLDT-8 increases OPG gene expression, decreases RANKL gene expression, increases the ratio of OPG to RANKL and inhibits RANKL-induced NF-κB expression in the current rat model of CIA.…”

“…RANK is located on the plasma membrane of osteoclast precursor cells, and the binding of RANKL to RANK promotes the differentiation and maturity of osteoclasts (38). The binding capacity of OPG to RANKL is higher than that of RANK to RANKL, which competitively binds RANKL, thereby competitively inhibiting its binding to RANK (39). Consequently, OPG may inhibit the differentiation of osteoclasts (39).…”

Vitamin D in rheumatoid arthritis—towards clinical application

“…87 In contrast to the reduction of RANKL expression by 1,25(OH) 2 D on leuko cytes, 58 the same metabolite was shown to increase RANKL expression in FLSs. 88 However, 1,25(OH) 2 D was also shown to enhance FLS-derived production of the RANKL decoy receptor osteoprotogerin (OPG) and increase the OPG:RANKL ratio. 88 Thus, 1,25(OH) 2 D might affect RA pathology by reducing osteoclast activation by FLSs.…”

Vitamin D and inflammation

“…However, it is clear that 25(OH)D concentration decline after major surgery. [13][14][15] [16][17][18] Animal studies also indicate 1,25(OH) 2 D 3 and its analogs are effective antiinflammatories. [19][20][21] The mechanisms by which 1,25(OH) 2 D 3 reduces inflammation are multiple.…”