{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:41:06Z","timestamp":1785415266191,"version":"3.56.0"},"reference-count":29,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institutes of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["RO1 AR078843-1A1"],"award-info":[{"award-number":["RO1 AR078843-1A1"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RO1 AR078843-1A1"],"award-info":[{"award-number":["RO1 AR078843-1A1"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","award":["IK6 BX005381"],"award-info":[{"award-number":["IK6 BX005381"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"award":["IK6 BX005381"],"award-info":[{"award-number":["IK6 BX005381"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>LRRK1 is essential for osteoclast-mediated bone resorption, and loss of LRRK1 function causes osteopetrosis in mice and humans. However, the mechanisms by which LRRK1 regulates osteoclast activity remain incompletely defined. We previously identified that phosphorylation of OSTM1 at threonine 328 and serine 329 was compromised in LRRK1-deficient osteoclasts. To test the role for OSTM1 phosphorylation in LRRK1 regulation of osteoclast functions, we expressed a phosphomimetic OSTM1 variant in LRRK1-null osteoclasts. Overexpression of phosphomimetic, but not a dephosphomimetic variant, partially restored resorptive activity in LRRK1-deficient osteoclasts in vitro. To test OSTM1\u2019s role in rescuing defective bone resorption in Lrrk1-null mice, we generated Ostm1-T328E\/S329D knock-in (KI) mice and crossed them onto the Lrrk1-deficient background. Ostm1-T328E\/S329D KI mice displayed normal skeletal development and bone remodeling. When crossed to the Lrrk1-deficient background, OSTM1-T328E\/S329D expression increased osteoclast resorptive activity and bone formation and partially improved trabecular architecture, although bone volume remained unchanged. These findings demonstrate that OSTM1 phosphorylation contributes to LRRK1-dependent regulation of osteoclast function and identify the LRRK1\u2013OSTM1 pathway as a mechanistic node controlling bone resorption. Our work provides new insight into the molecular basis of LRRK1-mediated osteoclast function and highlights OSTM1 phosphorylation as a potential therapeutic target for metabolic bone diseases.<\/jats:p>","DOI":"10.3390\/biology15120964","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expression of Phosphomimetic OSTM1-T328E\/S329D Variant Partially Restores Bone Resorption Defect in LRRK1-Deficient Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Anakha","family":"Udayakumar","sequence":"first","affiliation":[{"name":"The Musculoskeletal Disease Center, Jerry L Pettis VA Medical Center, Loma Linda, CA 92357, USA"},{"name":"Graduate Schools, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yian","family":"Chen","sequence":"additional","affiliation":[{"name":"The Musculoskeletal Disease Center, Jerry L Pettis VA Medical Center, Loma Linda, CA 92357, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0836-7555","authenticated-orcid":false,"given":"Haibo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Southern California Institute for Research and Education, Long Beach, CA 90815, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0063-986X","authenticated-orcid":false,"given":"Subburaman","family":"Mohan","sequence":"additional","affiliation":[{"name":"The Musculoskeletal Disease Center, Jerry L Pettis VA Medical Center, Loma Linda, CA 92357, USA"},{"name":"Department of Medicine, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weirong","family":"Xing","sequence":"additional","affiliation":[{"name":"The Musculoskeletal Disease Center, Jerry L Pettis VA Medical Center, Loma Linda, CA 92357, USA"},{"name":"Department of Medicine, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.rdc.2011.08.004","article-title":"Osteoporosis in men: Update 2011","volume":"37","author":"Orwig","year":"2011","journal-title":"Rheum. 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