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However, these transitions remain poorly understood due to cellular heterogeneity and limited spatial context. Here, we employed spatially resolved osteoblast-traced transcriptomics, integrating an osteoblast-specific lineage tracing study and spatially resolved laser-activated cell sorting (SLACS), to profile osteoblast states on quiescent bone surfaces. This approach identified transforming growth factor-beta (TGF-\u03b2) signaling as a regulator of osteoblast activation. We further validated this role using single-cell RNA sequencing, in vitro functional assays, and in vivo. In a hindlimb unloading mouse model, dual inhibition of TGF-\u03b2 and sclerostin enhanced bone mass and mitigated bone loss more effectively than sclerostin inhibition alone. These findings reveal a mechanistic role for TGF-\u03b2 in regulating osteoblast dynamics and propose a dual-target therapeutic strategy that enhances the efficacy of anti-sclerostin treatment in osteoporosis.<\/jats:p>","DOI":"10.1038\/s41413-026-00521-9","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:13:37Z","timestamp":1775103217000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Spatially resolved osteoblast-traced transcriptomics uncovers TGF-\u03b2 as a combination target with sclerostin in osteoporosis"],"prefix":"10.1038","volume":"14","author":[{"given":"Ahyoun","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Yeon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyejin","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangguo","family":"Che","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minkyeong","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongkuk","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoungseob","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunho","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Hye","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amos Chungwon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan Soo","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5057-8842","authenticated-orcid":false,"given":"Je-Yong","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-2142","authenticated-orcid":false,"given":"Jungwoo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunghoon","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9561-9110","authenticated-orcid":false,"given":"Sang Wan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"521_CR1","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/s41580-020-00279-w","volume":"21","author":"A Salhotra","year":"2020","unstructured":"Salhotra, A., Shah, H. 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