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The N-terminus of PTH has been investigated for decades for its ability to stimulate bone formation when administered intermittently (iPTH) and is used clinically as an effective anabolic agent for the treatment of osteoporosis. Despite great interest in iPTH and its clinical use, the mechanisms of PTH action remain complicated and not fully defined. More than 70 gene targets in more than 90 murine models have been utilized to better understand PTH anabolic actions. Because murine studies utilized wild-type mice as positive controls, a variety of variables were analyzed to better understand the optimal conditions under which iPTH functions. The greatest responses to iPTH were in male mice, with treatment starting later than 12\u2009weeks of age, a treatment duration lasting 5\u20136\u2009weeks, and a PTH dose of 30\u201360\u2009\u03bcg\/kg\/day. This comprehensive study also evaluated these genetic models relative to the bone formative actions with a primary focus on the trabecular compartment revealing trends in critical genes and gene families relevant for PTH anabolic actions. The summation of these data revealed the gene deletions with the greatest increase in trabecular bone volume in response to iPTH. These included PTH and 1-\u03b1-hydroxylase (Pth;1\u03b1(OH)ase, 62-fold), amphiregulin (Areg, 15.8-fold), and PTH related protein (Pthrp, 10.2-fold). The deletions with the greatest inhibition of the anabolic response include deletions of: proteoglycan 4 (Prg4, \u22129.7-fold), low-density lipoprotein receptor-related protein 6 (Lrp6, 1.3-fold), and low-density lipoprotein receptor-related protein 5 (Lrp5, \u22121.0-fold). Anabolic actions of iPTH were broadly affected via multiple and diverse genes. This data provides critical insight for future research and development, as well as application to human therapeutics. \u00a9 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4389","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T20:21:09Z","timestamp":1623183669000},"page":"1979-1998","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Anabolic actions of PTH in murine models: two decades of insights"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5696-4648","authenticated-orcid":false,"given":"Laura E.","family":"Zweifler","sequence":"first","affiliation":[{"name":"Department of Periodontics and Oral Medicine University of Michigan School of Dentistry Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7723-293X","authenticated-orcid":false,"given":"Amy J.","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Periodontics and Oral Medicine University of Michigan School of Dentistry Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6355-0710","authenticated-orcid":false,"given":"Stephanie","family":"Daignault-Newton","sequence":"additional","affiliation":[{"name":"Biostatistics Unit University of Michigan School of Public Health Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9173-9123","authenticated-orcid":false,"given":"Laurie K.","family":"McCauley","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical School University of Michigan Ann Arbor Michigan USA"},{"name":"Department of Periodontics and Oral Medicine University of Michigan School of Dentistry Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"issue":"12","key":"2024012713461365300_jbmr4389-bib-0001","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1007\/s40265-017-0780-7","article-title":"Abaloparatide: first global approval","volume":"77","author":"Shirley","year":"2017","journal-title":"Drugs"},{"issue":"2","key":"2024012713461365300_jbmr4389-bib-0002","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/aja.1000620203","article-title":"Variations produced in bones of growing rats by parathyroid extracts","volume":"62","author":"Burrows","year":"1938","journal-title":"Am J Anat"},{"issue":"3","key":"2024012713461365300_jbmr4389-bib-0003","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1113\/jphysiol.1932.sp002928","article-title":"The effect of parathyroid hormone and of irradiated ergosterol on calcium and phosphorous metabolism in the rat","volume":"76","author":"Pugsley","year":"1932","journal-title":"J Physiol"},{"issue":"1","key":"2024012713461365300_jbmr4389-bib-0004","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1113\/jphysiol.1933.sp003032","article-title":"The histological changes in the bone responsible for the action of parathyroid hormone on the calcium metabolism of the rat","volume":"79","author":"Pugsley","year":"1933","journal-title":"J Physiol"},{"issue":"1","key":"2024012713461365300_jbmr4389-bib-0005","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1084\/jem.49.1.145","article-title":"Studies of calcium and phosphorus metabolism: V. 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