Adiponectin regulates bone mass in AIS osteopenia via RANKL/OPG and IL6 pathway

Abstract

Background Osteopenia have been well documented in adolescent idiopathic scoliosis (AIS). Adiponectin has been shown to be inversely proportional to body mass index and to affect bone metabolism. However, the circulating levels of adiponectin and the relationship between adiponectin and low bone mass in AIS remain unclear. Methods A total of 563 AIS and 281 age-matched controls were recruited for this study. Anthropometry and bone mass were measured in all participants. Plasma adiponectin levels were determined by enzyme-linked immunosorbent assay (ELISA) in the AIS and control groups. An improved multiplex ligation detection reaction was performed to study on single nucleotide polymorphism. Facet joints were collected and used to measure the microstructure, the expression of RANKL, OPG, osteoblast-related genes, inflammatory factors, adiponectin and its receptors by qPCR, western blotting and immunohistochemistry. Furthermore, primary cells were extracted from facet joints to observe the reaction after adiponectin stimulation. Results Compared with the controls, lower body mass index and a marked increase in circulating adiponectin were observed in AIS osteopenia (17.09 ± 1.09 kg/m 2 and 21.63 ± 10.30 mg/L). A significant difference in the presence of rs7639352 was detected in the AIS osteopenia, AIS normal bone mass and control groups. The T allele showed a significant higher proportion in AIS osteopenia than AIS normal bone mass and control groups (41.75% vs 31.3% vs 25.7%, p < 0.05). micro-CT demonstrated that the AIS convex side had a significant lower bone volume than concave side. RNA and protein analyses showed that in cancellous bone, higher RANKL/OPG and adipoR1 levels and lower runx2 levels were observed, and in cartilage, higher adipoR1 and IL6 levels were observed in AIS. Furthermore, convex side had higher RANKL/OPG, IL6 and adipoR1 than concave side. Compared with normal primary cells, convex side primary cells showed the most acute action, and concave side primary cells showed the second-most acute action when exposed under same adiponectin concentration gradient. Conclusion Our results indicated that high circulating adiponectin levels may result from gene variations in AIS osteopenia. Adiponectin has a negative effect on bone metabolism, and this negative effect might be mediated by the ADR1-RANKL/OPG and ADR1-IL6 pathways. Electronic supplementary material The online version of this article (10.1186/s12967-019-1805-7) contains supplementary material, which is available to authorized users.

Adiponectin Deficiency Triggers Bone Loss by Up-Regulation of Osteoclastogenesis and Down-Regulation of Osteoblastogenesis

“…Our results showed that adiponectin deficiency induced a low bone mass by increased RANKL/OPG ratio that is opposite of a recent report (39). Zhang et al investigated the relationship between adiponectin and low bone mass in in patients with adolescent idiopathic scoliosis (AIS).…”

Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2

“…Dramatically reduced production of leptin, a potent inhibitor of bone formation (44,45), contributes, at least in part, to the high bone mass phenotype of the mutant mice. Adiponectin, an adipocyte-derived cytokine, exerts an inhibitory effect on bone metabolism (46,47). Because kindlin-2 loss dramatically reduced the blood levels of adiponectin ( Figure 4M), it is possible that the reduction in adiponectin also contributes to the high bone mass phenotype of the mutant mice.…”

Kindlin-2 regulates the differentiation of 3T3-L1 preadipocytes: implications for wound healing

“…In vivo, we verified that downregulation of kindlin-2 reduces the level of leptin and adiponectin which are two effective osteogenesis inhibitors. Therefore, the reduction of leptin and adiponectin may contribute to increased osteogenic differentiation (23)(24)(25)(26).…”