Histone demethylase LSD1 regulates bone mass by controlling WNT7B and BMP2 signaling in osteoblasts

Abstract

Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2. LSD1 deficiency resulted in increased BMP2 and WNT7B expression in osteoblasts and enhanced bone formation, while downregulation of WNT7B- and BMP2-related signaling using genetic mouse model or small-molecule inhibitors attenuated bone phenotype in vivo. Furthermore, the LSD1 inhibitor tranylcypromine (TCP) could increase bone mass in mice. These data identify LSD1 as a novel regulator of osteoblast activity and suggest LSD1 inhibition as a potential therapeutic target for treatment of osteoporosis.

Epigenetics: Taking the brakes off bone formation

A molecular brake controlling the differentiation of bone-forming osteoblasts has been identified, which could provide a new therapeutic target for osteoporosis. LSD1 regulates the expression of various genes by interfering with the ability of the cellular machinery to bind to DNA and transcribe it. A previous study had suggested that inhibiting LSD1 in stem cells from human fat promoted the formation of new osteoblasts. To further investigate its role in bone development, Weiguo Zou at the Shanghai Institute of Biochemistry and Cell Biology and colleagues engineered mice which lacked LSD1 in their mesenchymal cells–precursors of bone, muscle and fat cells—the animals had increased numbers of osteoblasts and greater bone mass. Further experiments revealed that blocking LSD1 resulted in increased expression of two osteoblast-stimulating factors, although it may also influence bone resorbing osteoclasts.

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