Chemerin located in bone marrow promotes osteogenic differentiation and bone formation via Akt/Gsk3β/β‐catenin axis in mice

Abstract

Chemerin, a secreted protein mainly produced by adipocytes and hepatocytes, plays a variety of roles in endocrine or paracrine signaling. As reported in human epidemiology, chemerin was correlated with osteoporosis. And the previous in vitro study found that chemerin knockdown promoted osteogenesis and inhibited adipogenesis. However, the function of chemerin in bone metabolism and the underlying mechanism remains unclear. In this study, we uncovered the in vivo function of chemerin in bone homeostasis. We discovered that in obese mice, chemerin was increased in serum, while decreased in the bone marrow; and the chemerin expression in bone tissue was positively correlated with osteogenic genes. To further investigate the function of chemerin in bone metabolism, we generated chemerin deficiency and overexpression mice. We found bone mass and osteogenesis were decreased in chemerin deficiency mice, while were increased in chemerin overexpression mice. Furthermore, we observed that the chemerin expression increased during osteogenic differentiation of MSCs. Besides, we verified that chemerin promoted osteogenic differentiation in C3H10T1/2 cells and BMSCs through Akt/Gsk3β/β‐catenin axis. Treatment with Akt inhibitor (MK2206) abolished the promoting effect of chemerin on osteogenic differentiation and active β‐catenin. Together, our results suggest chemerin in bone marrow, not in serum, promotes osteogenic differentiation and bone formation via Akt/Gsk3β/β‐catenin axis. Chemerin may serve as a therapeutic strategy for osteoporosis.

Loss of chemerin triggers bone remodeling in vivo and in vitro

“…Previous studies have reported that treatment with chemerin promoted osteoclastogenesis of hematopoietic stem cells (HSCs) in vitro [ [13] , 20 ], and increased bone resorption activity in mature osteoclasts [ 14 ]. Other investigators using chemerin or CMKLR1 knockout mice revealed that chemerin or CMKLR1 deficiency enhanced osteoclastic bone resorption and bone loss [ 9 , 19 ]. The cause for this discrepancy has not yet been identified.…”

“…While this paper was in revision, another report was published indicating that chemerin deficiency decreased osteogenesis and bone mass [ 9 ]. Although both studies highlight the effects of chemerin on bone metabolism, the two reports differ in the proposed effects of chemerin.…”

“…Our studies involved female mice fed a chow diet, while the other manuscript analyzed the effects of chemerin on male mice. Interestingly, in their analysis, they did observe that chemerin enhanced osteogenic differentiation in C3H10T1/2 cells and BMSCs through the Akt/Gsk3β/β-catenin axis [ 9 ]. Unfortunately, these pathways were not detected in our research.…”

MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin

“…Osteoporotic skeleton correlates with the development of obesity [32], excess glucocorticoid [33], and estrogen deficiency [34]-mediated marrow fat and visceral adipose accumulation. The molecular mechanism by which osteoporotic bone tissue dysregulates systemic adipose development warrants investigations.…”

Bone, fat, and muscle interactions in health and disease

“…Increase in adipogenesis at the expense of osteoblastogenesis (2), although animal models show osteogenic differentiation and bone formation (99).…”