Adiponectin Stimulates RANKL and Inhibits OPG Expression in Human Osteoblasts Through the MAPK Signaling Pathway

Abstract

Our study indicates that recombinant adiponectin induced RANKL and inhibited OPG expression in human osteoblasts through the AdipoR1/p38 MAPK pathway, and these responses contributed to the adiponectin-induced osteoclasts formation in the co-culture of osteoblast and peripheral blood monocytes systems. These findings showed that adiponectin increased osteoclast formation indirectly through stimulating RANKL and inhibiting OPG production in osteoblasts. It also suggests the pharmacological nature of recombinant adiponectin that indirectly induces osteoclasts formation. Introduction:Recently, adiponectin has emerged as an element in the regulation of bone metabolism, but the mechanism remains. This study was undertaken to investigate the action of adiponectin on osteoclastogenesis through revealing RANKL and osteoprotegerin (OPG) expression in osteoblasts and osteoclast formation. Materials and Methods: Real-time quantitative PCR and ELISA were used to detect RANKL and OPG mRNA and protein expression in cultured human osteoblasts. The involved signal pathway was studied using mitogen-activated protein kinase (MAPK) inhibitor and adiponectin receptor 1 (AdipoR1) siRNA. The effects of recombinant adiponectin on osteoclasts formation also were examined in the co-culture systems of osteoblast and peripheral blood monocytes (PBMCs) systems or purified CD14 + PBMCs cultures. Results: Our study showed that recombinant adiponectin induced RANKL and inhibited OPG mRNA expression in human osteoblasts in a dose-and time-dependent manner. Adiponectin also increased soluble RANKL and decreased OPG secretion in osteoblasts conditioned media. Suppression of AdipoR1 with siRNA abolished the adiponectin-regulated RANKL and OPG mRNA expression in osteoblasts. Furthermore, pretreatment of osteoblasts with the MAPK inhibitor SB203580 abolished adiponectin-regulated RANKL and OPG mRNA expression. Adiponectin induced osteoclast formation in the co-culture systems of osteoblast and PBMCs systems, and OPG entirely blocked this response. However, adiponectin had no direct effect on the differentiation of osteoclast precursor purified CD14 + PBMCs. Conclusions: These data indicate that recombinant adiponectin induced RANKL and inhibited OPG expression in human osteoblasts through the AdipoR1/p38 MAPK pathway, and these responses contributed to the adiponectin-induced osteoclast formation in the co-culture of osteoblast and PBMCs systems. These findings showed that adiponectin increased osteoclast formation indirectly through stimulating RANKL and inhibiting OPG production in osteoblasts. It suggests the pharmacological nature of recombinant adiponectin that indirectly induces osteoclasts formation.

Omentin-1, visfatin and adiponectin levels in relation to bone mineral density in Iranian postmenopausal women

“…We also found that age-and BMI-adjusted to the highest quartile versus the lowest quartile of adiponectin level had a significant association with lower OPG levels. This finding is consistent with previous in vitro [7] and in vivo studies [49].…”

“…via the p38 mitogen-activated protein kinase (MAPK) signaling pathway [43]. In contrast, adiponectin indirectly activates osteoclasts by stimulating RANKL and inhibiting OPG production in osteoblasts [7]. Adiponectin was associated with lower bone mass and decreased biomechanical measures of functional strength in growing mice [44].…”

“…It also plays an important role in glucose homeostasis and has anti-inflammatory and anti-atherogenic properties [6]. Adiponectin also influences osteoclastogenesis indirectly by stimulating the receptor activator of nuclear factor-κB ligand (RANKL) and inhibiting osteoprotegerin (OPG) production in osteoblasts [7].…”

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

“…For instance, adiponectin has been shown to stimulate proliferation, differentiation, and mineralization of osteoblasts. (44) Moreover, adiponectin stimulates RANKL expression from osteoblasts and increases osteoclastogenesis, (45) whereas adiponectin knockout mice have increased bone mass. (46) In addition, TNF-a is among the most potent of the osteoclastogenic cytokines produced in inflammation via its receptors on stromal or osteoblastic cells.…”

The role of resistin as a regulator of inflammation: Implications for various human pathologies

“…There is growing evidence that leptin as well as adiponectin can modulate bone metabolism [115,116,117].…”