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.
Highlights
Bone is a dynamic organ that supports locomotive activity, maintains blood calcium levels, serves as a reservoir for hematopoietic stem cells, and houses the brain and spinal cord.The maintenance of bone is accomplished by continuous remodeling throughout life via the balanced activity of mesenchymally derived osteoblasts and hematopoietically derived osteoclasts.[1]
Inhibition of LSD1 using the small inhibitor tranylcypromine (TCP) increased bone mass in mice. These findings provide strong in vivo evidence for the role of LSD1 as a repressor of osteoblastogenesis through repressing BMP2 and WNT7B expression and reveal it as a potential therapeutic target for osteoporosis
HMSCs transduced with four different shRNA lentivirus constructs targeting human LSD1 were cultured in osteoblast differentiation media
Summary
Bone is a dynamic organ that supports locomotive activity, maintains blood calcium levels, serves as a reservoir for hematopoietic stem cells, and houses the brain and spinal cord. The maintenance of bone is accomplished by continuous remodeling throughout life via the balanced activity of mesenchymally derived osteoblasts and hematopoietically derived osteoclasts.[1] Osteoblasts are the bone-forming cells, which synthesize collagens and proteins such as osteocalcin and osteopontin to form bone matrix while osteoclasts resorb bone in response to microfractures. LSD1 has been shown to promote nuclear hormone receptor induced transcription via H3K9me1/ me[2] demethylation.[4,5] Germline deletion of Lsd[1] in mice results in embryonic lethality and embryonic stem cells lacking LSD1 show impaired differentiation potential indicating an important role for LSD1 during embryogenesis.[6,7] LSD1 orchestrates the emergence and differentiation of hematopoietic stem cells, 8–10 regulates fat metabolism and modulates p53 signaling pathway.[11,12] In addition, LSD1 has been associated with multiple human malignancies including prostate cancer, bladder cancer, leukemia, and others.[13,14] Because of the important role of LSD1 in these diseases, pharmacological LSD1 inhibitors have been developed.[15,16,17] A recent study showed that inhibition of LSD1 in human adipose-derived stem cells (hASCs) using LSD1 inhibitors enhanced osteoblastogenesis,[18] but the precise in vivo role of LSD1 in bone development and remodeling remains to be determined
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