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The multi-kinase inhibitor YKL-05\u2013099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05\u2013099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05\u2013099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05\u2013099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05\u2013099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2\/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.<\/jats:p>","DOI":"10.7554\/elife.67772","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T08:00:56Z","timestamp":1624435256000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.67772","source":"Crossref","is-referenced-by-count":27,"title":["Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption"],"prefix":"10.7554","volume":"10","author":[{"given":"Cheng-Chia","family":"Tang","sequence":"first","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian D","family":"Castro Andrade","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard 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