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Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi\u2010potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic\u2010induced fracture, systemic adiposity, and the presence of bone\u2010homing cancers. Herein we provide evidence that signals from the bone matrix (osteocytes) determine marrow adiposity by regulating adipogenesis in the bone marrow. Specifically, we found that physiologically relevant levels of Sclerostin (SOST), which is a Wnt\u2010inhibitory molecule secreted from bone matrix\u2010embedded osteocytes, can induce adipogenesis in 3T3\u2010L1 cells, mouse ear\u2010 and BM\u2010derived MSCs, and human BM\u2010derived MSCs. We demonstrate that the mechanism of SOST induction of adipogenesis is through inhibition of Wnt signaling in pre\u2010adipocytes. We also demonstrate that a decrease of sclerostin in vivo, via both genetic and pharmaceutical methods, significantly decreases bone marrow adipose tissue (BMAT) formation. Overall, this work demonstrates a direct role for SOST in regulating fate determination of BM\u2010adipocyte progenitors. This provides a novel mechanism for which BMAT is governed by the local bone microenvironment, which may prove relevant in the pathogenesis of certain diseases involving marrow adipose. Importantly, with anti\u2010sclerostin therapy at the forefront of osteoporosis treatment and a greater recognition of the role of BMAT in disease, these data are likely to have important clinical implications.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.25976","type":"journal-article","created":{"date-parts":[[2017,5,1]],"date-time":"2017-05-01T22:04:21Z","timestamp":1493676261000},"page":"1156-1167","source":"Crossref","is-referenced-by-count":143,"title":["The skeletal cell\u2010derived molecule sclerostin drives bone marrow adipogenesis"],"prefix":"10.1002","volume":"233","author":[{"given":"Heather","family":"Fairfield","sequence":"first","affiliation":[{"name":"Center for Clinical and Translational Research Maine Medical Center Research Institute Scarborough Maine"},{"name":"University of Maine Graduate School of Biomedical Science and Engineering Orono Maine"},{"name":"Tufts University School of Medicine Boston 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