{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T21:57:27Z","timestamp":1785794247198,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGF\u03b2 (LAP-TGF\u03b2) as an inhibitor of TGF\u03b2 activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.<\/jats:p>","DOI":"10.3390\/cancers13225593","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T10:44:58Z","timestamp":1636454698000},"page":"5593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells"],"prefix":"10.3390","volume":"13","author":[{"given":"Ke-Xin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China"},{"name":"Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China"},{"name":"Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1853-0216","authenticated-orcid":false,"given":"Bai-Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7881-8959","authenticated-orcid":false,"given":"Hiroki","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China"},{"name":"Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA"},{"name":"Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/nm.2452","article-title":"Evidence for osteocyte regulation of bone homeostasis through RANKL expression","volume":"17","author":"Nakashima","year":"2011","journal-title":"Nat. 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