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The mechanism governing lineage allocation of SSPCs is still not completely understood. Hedgehog (Hh) signaling plays an essential role in specifying osteogenic fate of mesenchymal progenitors during embryogenesis. However, it is still unclear whether Hh signaling is required for lineage allocation of SSPCs in postnatal skeleton, and whether its dysregulation is related to age-related osteoporosis. Here, we demonstrated that Hh signaling was activated in metaphyseal SSPCs during osteogenic differentiation in the adult skeleton, and its activity decreased with aging. Inactivation of Hh signaling by genetic ablation of Smo, a key molecule in Hh signaling, in Osx-Cre\u2013targeted SSPCs and hypertrophic chondrocytes led to decreased bone formation and increased bone marrow adiposity, two key pathological features of age-related osteoporosis. Moreover, we found that the bone-fat imbalance phenotype caused by Smo deletion mainly resulted from aberrant allocation of SSPCs toward adipogenic lineage at the expense of osteogenic differentiation, but not due to accelerated transdifferentiation of chondrocytes into adipocytes. Mechanistically, we found that Hh signaling regulated osteoblast versus adipocyte fate of SSPCs partly through upregulating Wnt signaling. Thus, our results indicate that Hh signaling regulates bone homeostasis and age-related osteoporosis by acting as a critical switch of cell fate decisions of Osx-Cre\u2013targeted SSPCs in mice and suggest that Hh signaling may serve as a potential therapeutic target for the treatment of osteoporosis and other metabolic bone diseases. \u00a9 2021 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4485","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T05:46:10Z","timestamp":1638769570000},"page":"559-576","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Hedgehog Signaling Controls Bone Homeostasis by Regulating Osteogenic\/Adipogenic Fate of Skeletal Stem\/Progenitor Cells in Mice"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0515-9841","authenticated-orcid":false,"given":"Liwei","family":"Zhang","sequence":"first","affiliation":[{"name":"Orthopedic Institute, Medical College Soochow University Suzhou China"},{"name":"Orthopedic Department Taizhou Hospital Affiliated to Wenzhou Medical University Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejie","family":"Fu","sequence":"additional","affiliation":[{"name":"Orthopedic Institute, Medical College Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The First Affiliated Hospital of Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cunchang","family":"Liu","sequence":"additional","affiliation":[{"name":"Orthopedic Institute, Medical College Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Orthopedic Institute, Medical College Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongji","family":"You","sequence":"additional","affiliation":[{"name":"Orthopedic Institute, Medical College Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[{"name":"Orthopedic Institute, Medical College Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Xiu","sequence":"additional","affiliation":[{"name":"Orthopedic Institute, Medical College Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Orthopedic 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