{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:46:24Z","timestamp":1768527984277,"version":"3.49.0"},"posted":{"date-parts":[[2025,9,8]]},"group-title":"Cell Biology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100001742","name":"United States-Israel Binational Science Foundation","doi-asserted-by":"crossref","award":["2021168"],"award-info":[{"award-number":["2021168"]}],"id":[{"id":"10.13039\/501100001742","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Intramural Research Program of the National Institutes of Health"},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R00-HD110609"],"award-info":[{"award-number":["R00-HD110609"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The skeleton is a living, biological tissue responding to the biomechanical demands placed upon it throughout life. The individual bones creating this physiological system are each shaped by a multinucleated cell type - the osteoclast - that sculpts each bone in collaboration with local cellular partners, which offer chemical and even tactile feedback of many sorts. Unfortunately, the perturbation of osteoclast formation and function underpins a broad range of human skeletal pathologies, including osteopetrosis - a systemic pathology characterized by impaired osteoclast resorption leading to skeletal thickening, brittle bones, frailty, and lethality. Here, we describe a molecular dysfunction observed in murine and human models of two forms of osteoclast-rich, autosomal recessive osteopetrosis, and our approach for exploiting this molecular dysfunction to correct pathologic osteoclast hyperfusion and resorptive impairment. We find that La - a manager of osteoclast fusion and subsequent resorptive activity - is greatly elevated at the surface of osteoclasts upon loss of\n                  <jats:italic>SNX10<\/jats:italic>\n                  or\n                  <jats:italic>OSTM1<\/jats:italic>\n                  . Using inhibitory antibodies, we suppress excessive La surface function in these mutant osteoclasts, impede osteopetrotic hyperfusion and restore osteoclast resorptive function. We share these observations as proofs-of-principle that osteoclast fusion represents a viable therapeutic target for addressing osteoclast dysfunction in diseases underpinned by excessive osteoclast multinucleation and perturbed resorptive function.\n                <\/jats:p>","DOI":"10.1101\/2025.09.07.674639","type":"posted-content","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T12:20:23Z","timestamp":1757334023000},"source":"Crossref","is-referenced-by-count":0,"title":["Elevated surface La promotes hyperfusion and contributes to impaired resorption in osteopetrosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5886-2047","authenticated-orcid":false,"given":"Jarred 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