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Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4fl\/fl) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+\u00a0to remove Nmp4 from mesenchymal stem\/progenitor cells (MSPCs) in long bones; (ii) BglapCre+\u00a0targeting mature osteoblasts, and (iii) Dmp1Cre+\u00a0to disable Nmp4 in osteocytes. Virgin female Cre+\u00a0and Cre\u2212 mice (10\u2009weeks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1-34 at 30\u2009\u03bcg\/kg or vehicle for 4\u2009weeks or 7\u2009weeks. Skeletal response was assessed using dual-energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and serum analysis for remodeling markers. Nmp4fl\/fl;Prx1Cre+\u00a0mice virtually phenocopied the global Nmp4\u2212\/\u2212 skeleton in the femur, ie, a mild baseline phenotype but significantly enhanced PTH-induced increase in femur trabecular bone volume\/total volume (BV\/TV) compared with their Nmp4fl\/fl;Prx1Cre\u2212 controls. This was not observed in the spine, where Prrx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl\/fl;BglapCre+) failed to increase BV\/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl\/fl;Dmp1Cre+) increased BV\/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4\u2212\/\u2212 Prx1-expressing MSPCs drive the improved response to PTH therapy and that this gene has stage-specific effects on osteoanabolism. \u00a9 2022 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4732","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T03:10:26Z","timestamp":1667358626000},"page":"70-85","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation"],"prefix":"10.1093","volume":"38","author":[{"given":"Emily G.","family":"Atkinson","sequence":"first","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Adaway","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Horan","sequence":"additional","affiliation":[{"name":"Richard L. Roudebush Veterans Affairs Medical Center Indianapolis IN USA"},{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Korff","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Klunk","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley L.","family":"Orr","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, College of Osteopathic Medicine Marian University Indianapolis Indianapolis IN USA"},{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Ratz","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, College of Osteopathic Medicine Marian University Indianapolis Indianapolis IN USA"},{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8203-7004","authenticated-orcid":false,"given":"Teresita","family":"Bellido","sequence":"additional","affiliation":[{"name":"Central Arkansas Veterans Healthcare System Little Rock AR USA"},{"name":"Department of Physiology and Cell BiologyUniversity of Arkansas for Medical Sciences (UAMS) Little Rock AR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9537-4544","authenticated-orcid":false,"given":"Lilian I.","family":"Plotkin","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine (IUSM) Indianapolis IN USA"},{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Robling","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine (IUSM) Indianapolis IN USA"},{"name":"Richard L. Roudebush Veterans Affairs Medical Center Indianapolis IN USA"},{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8886-6842","authenticated-orcid":false,"given":"Joseph P.","family":"Bidwell","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine (IUSM) Indianapolis IN USA"},{"name":"Department of Anatomy, Cell Biology, and Physiology Indiana University School of Medicine (IUSM) Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"issue":"10","key":"2024012714091100500_jbmr4732-bib-0001","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1007\/s40266-017-0492-4","article-title":"Pain in osteoporosis: from pathophysiology to therapeutic 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