{"doi":"10.1016/j.bone.2025.117695","title":"Loss of Tsc1 in Osterix-expressing cells leads to greater bone mass and strength in mice","abstract":"Tuberous sclerosis complex 1 (Tsc1) negatively regulates mTORC1 signaling, but its role in postnatal skeletal development is not fully understood. Previous studies using various Cre drivers to target osteoblasts or mesenchymal lineage cells have generally shown higher bone mass accompanied by disorganized bone structure. However, our earlier study using Osx-Cre-mediated Tsc1 deletion demonstrated that conditional knockout mice (CKO) had lower femoral trabecular bone at one month of age, but early lethality prevented later-stage assessment. Furthermore, how postnatal mTOCRC1 hyperactivation affects bone accrual and mechanical properties remains unknown. In this report, we first evaluated the cortical bone phenotype of one-month-old CKO mice using nanoCT, immunostaining, and quantitative PCR (qPCR). CKO mice exhibited greater cortical bone mass, elevated osteoblast markers (Alpl, Bsp, Col1a1, Ocn) and transcription factors (Runx2, Osx), enhanced periosteal proliferation in vivo, and upregulated proliferation of primary femur cortical bone-derived osteoblasts in vitro. To overcome early lethality and assess the impact of postnatal mTORC1 hyperactivation, we utilized the built-in doxycycline (Dox) Turn-Off system in Osx-Cre mice to suppress Cre activity until 2 months of age. Postnatal Tsc1 deletion from 2 to 5 months led to robust cortical and trabecular bone gains in the femur, calvariae, and vertebrae. Picrosirius Red staining demonstrated that the femoral cortical bone in CKO mice exhibited organized collagen with lamellar features, indicating preserved tissue quality. Importantly, four-point bending tests demonstrated significantly improved femoral mechanical strength in CKO mice. In summary, our data reveal differential effects of Tsc1 deletion on trabecular and cortical bone at an early postnatal stage, and show that postnatal deletion results in robust bone gain with enhanced mechanical strength. These findings provide a more complete understanding of Tsc1-mTORC1 signaling as a key regulator of bone mass and challenge the assumption that mTORC1 hyperactivation yields mechanically inferior bone.","journal":"Bone","year":2025,"id":548143,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9493,"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":454290,"name":"Thomas Kim","orcid":"0000-0001-6282-0803","position":1,"is_corresponding":false},{"id":793266,"name":"Xiaoxi Wei","orcid":"0000-0002-4387-9161","position":2,"is_corresponding":false},{"id":440113,"name":"Karl J. Jepsen","orcid":"0000-0002-2903-9940","position":3,"is_corresponding":false},{"id":75986,"name":"Yuji Mishina","orcid":"0000-0002-6268-4204","position":4,"is_corresponding":false},{"id":1441346,"name":"Nicholas Auyeung","orcid":null,"position":5,"is_corresponding":false},{"id":607953,"name":"Fei Liu","orcid":"0009-0009-6085-2823","position":6,"is_corresponding":false},{"id":370341,"name":"Han Kyoung Choi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":21,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41176199","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":[]}