{"doi":"10.1172/jci142580","title":"Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts","abstract":"Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.","journal":"Journal of Clinical Investigation","year":2021,"id":182630,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":391458,"name":"Larry D. Mesner","orcid":null,"position":1,"is_corresponding":false},{"id":464982,"name":"Gina M. Calabrese","orcid":"0000-0002-9092-2396","position":2,"is_corresponding":false},{"id":735075,"name":"Naomi Dirckx","orcid":"0000-0001-6507-8106","position":3,"is_corresponding":false},{"id":685173,"name":"Li Zhu","orcid":"0000-0002-4919-1894","position":4,"is_corresponding":false},{"id":735076,"name":"Angela Verardo","orcid":"0000-0002-0203-279X","position":5,"is_corresponding":false},{"id":735077,"name":"Qian Yang","orcid":"0000-0003-1651-0294","position":6,"is_corresponding":false},{"id":232245,"name":"Robert J. Tower","orcid":"0000-0001-5856-5758","position":7,"is_corresponding":false},{"id":735656,"name":"Marie–Claude Faugere","orcid":null,"position":8,"is_corresponding":false},{"id":24960,"name":"Charles R. Farber","orcid":"0000-0002-6748-4711","position":9,"is_corresponding":false},{"id":287434,"name":"Thomas L. Clemens","orcid":null,"position":10,"is_corresponding":false},{"id":585518,"name":"Qian Zhang","orcid":"0000-0001-9205-1881","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:48:13.605421Z","pmid":"33792563","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":[]}