{"doi":"10.1101/2025.07.11.664289","title":"Estrogens protect bone mass by inhibiting NAD <sup>+</sup> metabolism in osteoclasts","abstract":"Abstract Estrogens protect against bone loss by reducing osteoclast number and bone resorption, primarily via direct actions on osteoclast precursors. In these cells, estrogens attenuate RANKL-induced stimulation of mitochondrial complex I, which is crucial for ATP generation through NADH oxidation. NAD + promotes redox reactions and activates NAD + -dependent enzymes, including the mitochondrial deacetylase SIRT3. However, the contribution of NAD + to the skeletal effects of estrogens remains unknown. We show that NAD + levels and SIRT3 activity are upregulated by RANKL and inhibited by 17β-estradiol (E 2 ) in mouse and human osteoclast precursors. Increasing NAD + or the mitochondrial NAD + /NADH ratio reverses the inhibitory effects of E 2 on SIRT3 activity and osteoclastogenesis in vitro . Deletion of Nampt , a key NAD salvage enzyme, reduces NAD + and prevents bone loss in ovariectomized mice. Similarly, deletion of Sirt3 in osteoclast precursors mitigates estrogen deficiency–induced bone resorption. These findings indicate that suppression of NAD + levels and mitochondrial redox metabolism by estrogens contributes to their anti-resorptive effects via inhibition of SIRT3.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":570458,"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":0.9516,"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":1228584,"name":"Gareeballah Osman Adam","orcid":"0000-0002-8650-8117","position":1,"is_corresponding":false},{"id":1429981,"name":"Ankita Chalke","orcid":null,"position":2,"is_corresponding":false},{"id":1476050,"name":"Ana Resende-Coelho","orcid":null,"position":3,"is_corresponding":false},{"id":1071394,"name":"Olivia Reyes‐Castro","orcid":null,"position":4,"is_corresponding":false},{"id":281435,"name":"Aaron Warren","orcid":"0000-0002-0042-9021","position":5,"is_corresponding":false},{"id":1476051,"name":"Luis F Grilo","orcid":null,"position":6,"is_corresponding":false},{"id":115405,"name":"Claudia C.S. Chini","orcid":null,"position":7,"is_corresponding":false},{"id":1476052,"name":"Benjamin Stronach","orcid":null,"position":8,"is_corresponding":false},{"id":1066503,"name":"Benjamin M. Stronach","orcid":"0000-0003-2554-5157","position":9,"is_corresponding":false},{"id":378859,"name":"Elena Ambrogini","orcid":"0000-0002-5704-6072","position":10,"is_corresponding":false},{"id":1476053,"name":"Eduardo N Chini","orcid":null,"position":11,"is_corresponding":false},{"id":237866,"name":"Ha‐Neui Kim","orcid":"0000-0003-2498-6700","position":12,"is_corresponding":false},{"id":237879,"name":"Maria Almeida","orcid":"0000-0002-6722-9200","position":13,"is_corresponding":false},{"id":1229035,"name":"Adriana Marques-Carvalho","orcid":null,"position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:57:07.857542Z","pmid":"40791440","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":[]}