Salt-inducible kinase 1 regulates bone anabolism via the CRTC1–CREB–Id1 axis

Min Kyung Kim, Jun Oh Kwon, Min Kyoung Song, Bongjun Kim, Haemin Kim, Zang Hee Lee, Seung Hoi Koo, Hong Hee Kim

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Abstract

New bone anabolic agents for the effective treatment of bone metabolic diseases like osteoporosis are of high clinical demand. In the present study, we reveal the function of salt-inducible kinase 1 (SIK1) in regulating osteoblast differentiation. Gene knockdown of SIK1 but not of SIK2 or SIK3 expression in primary preosteoblasts increased osteoblast differentiation and bone matrix mineralization. SIK1 also regulated the proliferation of osteoblastic precursor cells in osteogenesis. This negative control of osteoblasts required the catalytic activity of SIK1. SIK1 phosphorylated CREB regulated transcription coactivator 1 (CRTC1), preventing CRTC1 from enhancing CREB transcriptional activity for the expression of osteogenic genes like Id1. Furthermore, SIK1 knockout (KO) mice had higher bone mass, osteoblast number, and bone formation rate versus littermate wild-type (WT) mice. Preosteoblasts from SIK1 KO mice showed more osteoblastogenic potential than did WT cells, whereas osteoclast generation among KO and WT precursors was indifferent. In addition, bone morphogenic protein 2 (BMP2) suppressed both SIK1 expression as well as SIK1 activity by protein kinase A (PKA)–dependent mechanisms to stimulate osteogenesis. Taken together, our results indicate that SIK1 is a key negative regulator of preosteoblast proliferation and osteoblast differentiation and that the repression of SIK1 is crucial for BMP2 signaling for osteogenesis. Therefore, we propose SIK1 to be a useful therapeutic target for the development of bone anabolic strategies.

Original languageEnglish
Article number826
JournalCell Death and Disease
Volume10
Issue number11
DOIs
Publication statusPublished - 2019 Nov 1

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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  • Cite this

    Kim, M. K., Kwon, J. O., Song, M. K., Kim, B., Kim, H., Lee, Z. H., Koo, S. H., & Kim, H. H. (2019). Salt-inducible kinase 1 regulates bone anabolism via the CRTC1–CREB–Id1 axis. Cell Death and Disease, 10(11), [826]. https://doi.org/10.1038/s41419-019-1915-4