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The calcium stress was initiated by feeding cKO mutants and wildtype (WT) littermates a calcium-deficient diet for 2\u00a0weeks. Deletion of\n                    <jats:italic>Grem1<\/jats:italic>\n                    in mature osteoclasts did not affect developmental bone growth nor basal bone turnover. In response to calcium depletion, male cKO mutants showed greater increases in osteoclastic resorption and trabecular bone loss than male WT littermates, indicating an enhanced skeletal sensitivity to calcium depletion in male mutants. The enhanced sensitivity to calcium depletion was sex-dependent, as female cKO mutants showed lower increases in osteoclastic resorption and bone loss than female WT littermates as well as male cKO mutants. The sex disparity in osteoclastic resorption response to calcium stress was intrinsic to osteoclasts since osteoclasts of male but not female cKO mutants showed greater in vitro bone resorption activity than osteoclasts of WT littermates of respective sex. Male cKO mutants displayed smaller bone formation response to calcium depletion than male WT littermates, while female mutants showed bigger bone formation response than female WT littermates, indicating that cKO mutants also displayed sex disparity in bone formation response. The sex disparity in bone formation response was not caused by intrinsic differences in osteoblasts but might be due to sex-dependent differential osteoclastic release of osteogenic factors. In summary, osteoclast-derived gremlin-1 has complicated and sex-dependent regulatory roles in skeletal response to calcium stress.\n                  <\/jats:p>","DOI":"10.1007\/s00223-024-01337-7","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T12:06:19Z","timestamp":1736424379000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Conditional Deletion of Gremlin-1 in Cathepsin K-expressing Mature Osteoclasts Altered the Skeletal Response to Calcium Depletion in Sex-Dependent Manner"],"prefix":"10.1007","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-7008","authenticated-orcid":false,"given":"Matilda H.-C.","family":"Sheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4691-8143","authenticated-orcid":false,"given":"Charles H.","family":"Rundle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9526-7995","authenticated-orcid":false,"given":"David J.","family":"Baylink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1109-5052","authenticated-orcid":false,"given":"Kin-Hing William","family":"Lau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"1337_CR1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1753-4887.1989.tb02794.x","volume":"47","author":"BE Nordin","year":"1989","unstructured":"Nordin BE, Morris HA (1989) The calcium deficiency model for osteoporosis. 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Sheng, Charles H. Rundle, David J. Baylink, and Kin-Hing William Lau) state that they have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"The animal protocol (protocol #1298) was reviewed and approved by the Animal Care and Use Committee (IACUC) of VA Loma Linda Healthcare System as well as by the IACUC of the Loma Linda University and the Animal Care and Use Review Office (ACURO) of the US Army Medical Research and Materiel Command of the Department of Defense. In conducting research using animals, the investigators adhered to the Animal Welfare Act Regulations and other federal statures relating to animals and animal experimentation and the principles set forth in the current version of the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA Molecules.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 Human and Animal Rights and Informed Consent"}},{"value":"The views, opinions and\/or findings contained in this report are those of the authors and should not be construed as an official position, policy or decision of the US Army or the United States government, unless so designated by other documentation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclaimers"}}],"article-number":"28"}}