{"doi":"10.1101/2025.09.07.674639","title":"Elevated surface La promotes hyperfusion and contributes to impaired resorption in osteopetrosis","abstract":"Abstract 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 SNX10 or OSTM1 . 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574367,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":658134,"name":"Evgenia Leikina","orcid":"0009-0001-5172-5963","position":1,"is_corresponding":false},{"id":319293,"name":"Hongyin Wang","orcid":null,"position":2,"is_corresponding":false},{"id":1328598,"name":"Wendy Zhang","orcid":"0009-0006-9245-1184","position":3,"is_corresponding":false},{"id":1477650,"name":"Griffin Katz","orcid":null,"position":4,"is_corresponding":false},{"id":1481770,"name":"Nina Reuven","orcid":"0000-0003-1569-3818","position":5,"is_corresponding":false},{"id":1481771,"name":"Ari Elson","orcid":"0000-0001-9808-9135","position":6,"is_corresponding":false},{"id":41048,"name":"Benjamin Geiger","orcid":"0000-0001-8559-6373","position":7,"is_corresponding":false},{"id":637776,"name":"Leonid Chernomordik","orcid":"0000-0001-7131-9244","position":8,"is_corresponding":false},{"id":637775,"name":"Jarred M. Whitlock","orcid":"0000-0002-5886-2047","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:57:40.686992Z","pmid":"40964326","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}