{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T17:41:23Z","timestamp":1784655683666,"version":"3.55.0"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX003025"],"award-info":[{"award-number":["I01BX003025"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["IK6-BX006479"],"award-info":[{"award-number":["IK6-BX006479"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>High circulating parathyroid hormone (PTH) leading to secondary hyperparathyroidism is proposed to be a key driver of the skeletal phenotype of chronic kidney disease-mineral bone disorder (CKD-MBD) leading to high bone turnover and cortical bone deterioration. The association between high PTH and the skeletal phenotype is typically clearly demonstrated in preclinical models of CKD; however, clinical studies show the relationship between PTH and skeletal outcomes is not as clear. The clinical data have led to a proposed hyporesponsiveness to PTH in the CKD setting with unclear causes. In the current study, we assessed skeletally mature male C57BL\/6J mice at 12-weeks and 21-weeks of adenine-induced CKD (Ad) with the second timepoint seven weeks longer than we have previously assessed. We found that serum BUN was high in Ad mice in both groups indicating the presence of kidney disease while PTH was higher in 21-wk Ad vs. 12-wk Ad. Despite the higher PTH, bone formation rate in 21-wk Ad mice was lower than 21-wk Ad mice. Additionally, immunohistochemical assessment of the PTH receptor, PTHR1, and RANKL, a key factor upregulated by PTH, showed a lower percentage of osteocytes positive for the proteins in 21-wk Ad vs. 12-wk Ad. Furthermore, regression analyses demonstrated a positive relationship between serum PTH and PTHR1 and RANKL at 12-weeks, but this relationship was lost by 21-weeks. Overall, these data indicate that prolonged exposure to continuously elevated PTH in adenine-induced CKD mice eventually led to an altered skeletal response indicating lower responsiveness of bone, particularly osteocytes, to the chronic PTH signal. This has implications for using PTH as a surrogate marker of bone outcomes in CKD as well as pointing to the need to better understand the time-based relationship between PTH and skeletal outcomes in CKD.<\/jats:p>","DOI":"10.1371\/journal.pone.0324628","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T17:53:56Z","timestamp":1748022836000},"page":"e0324628","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Prolonged secondary hyperparathyroidism in adenine-induced CKD leads to skeletal changes consistent with skeletal hyporesponsiveness to PTH"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2944-8082","authenticated-orcid":true,"given":"Corinne E.","family":"Metzger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Landon 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