{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:03:48Z","timestamp":1791270228089,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2012,12,13]],"date-time":"2012-12-13T00:00:00Z","timestamp":1355356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We studied mice with or without heterozygous deletion of the Casr in the parathyroid gland (PTG) [PTGCaSR(+\/\u2013)] to delineate effects of age and sex on manifestations of hyperparathyroidism (HPT). In control mice, aging induced a left-shift in the Ca2+\/parathyroid hormone (PTH) set point accompanied by increased PTG CaSR expression along with lowered serum Ca2+ and mildly increased PTH levels, suggesting adaptive responses of PTGs to aging-induced changes in mineral homeostasis. The aging effects on Ca2+\/PTH set point and CaSR expression were significantly blunted in PTGCaSR(+\/\u2013) mice, who showed instead progressively elevated PTH levels with age, especially in 12-month-old females. These 12-month-old knockout mice demonstrated resistance to their high PTH levels in that serum 1,25-dihydroxyvitamin D (1,25-D) levels and RNA expression of renal Cyp27b1 and expression of genes involved in Ca2+ transport in kidney and intestine were unresponsive to the rising PTH levels. Such changes may promote negative Ca2+ balance, which further exacerbate the HPT. Skeletal responses to HPT were age-, sex-, and site-dependent. In control mice of either sex, trabecular bone in the distal femur decreased whereas cortical bone in the tibiofibular junction increased with age. In male PTGCaSR(+\/\u2013) mice, anabolic actions of the elevated PTH levels seemed to protect against trabecular bone loss at \u22653 months of age at the expense of cortical bone loss. In contrast, HPT produced catabolic effects on trabecular bone and anabolic effects on cortical bone in 3-month-old females; but these effects reversed by 12 months, preserving trabecular bone in aging mice. We demonstrate that the CaSR plays a central role in the adaptive responses of parathyroid function to age-induced changes in mineral metabolism and in target organ responses to calciotropic hormones. Restraining the ability of the PTG to upregulate CaSRs by heterozygous gene deletion contributes to biochemical and skeletal manifestations of HPT, especially in aging females. \u00a9 2013 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1846","type":"journal-article","created":{"date-parts":[[2012,12,13]],"date-time":"2012-12-13T15:01:57Z","timestamp":1355410917000},"page":"1087-1100","source":"Crossref","is-referenced-by-count":29,"title":["Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice"],"prefix":"10.1093","volume":"28","author":[{"given":"Zhiqiang","family":"Cheng","sequence":"first","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Liang","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsui-Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Li","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Santa Maria","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"You","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanson","family":"Ho","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuqing","family":"Song","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bikle","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chialing","family":"Tu","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Shoback","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhan","family":"Chang","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,12,13]]},"reference":[{"issue":"1","key":"2024020318404388800_bib1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1152\/physrev.2001.81.1.239","article-title":"Extracellular calcium sensing and extracellular calcium signaling","volume":"81","author":"Brown","year":"2001","journal-title":"Physiol Rev."},{"key":"2024020318404388800_bib2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/978-1-4020-6191-2_6","article-title":"The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics","volume":"45","author":"Brown","year":"2007","journal-title":"Subcell Biochem."},{"issue":"3","key":"2024020318404388800_bib3","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ceca.2003.10.012","article-title":"Extracellular Ca2+-sensing receptors--an overview","volume":"35","author":"Chang","year":"2004","journal-title":"Cell Calcium."},{"issue":"4","key":"2024020318404388800_bib4","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1111\/j.1523-1755.2005.00587.x","article-title":"Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone","volume":"68","author":"van Abel","year":"2005","journal-title":"Kidney Int."},{"issue":"1","key":"2024020318404388800_bib5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.abb.2008.06.006","article-title":"Specific regulation of CYP27B1 and VDR in proximal versus distal renal cells","volume":"477","author":"Bajwa","year":"2008","journal-title":"Arch Biochem Biophys."},{"issue":"12","key":"2024020318404388800_bib6","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.tibs.2004.10.005","article-title":"Enzymes involved in the activation and inactivation of vitamin D","volume":"29","author":"Prosser","year":"2004","journal-title":"Trends Biochem Sci."},{"issue":"(2 Pt 2","key":"2024020318404388800_bib7","first-page":"F157","author":"Brown","year":"1999","journal-title":"Am J Physiol."},{"issue":"2","key":"2024020318404388800_bib8","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/S0003-9861(02)00636-7","article-title":"Hormonal regulation of 25-hydroxyvitamin D3-1alpha-hydroxylase and 24-hydroxylase gene transcription in opossum kidney cells","volume":"409","author":"Armbrecht","year":"2003","journal-title":"Arch Biochem Biophys."},{"issue":"(Pt 3","key":"2024020318404388800_bib9","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1113\/jphysiol.2003.043349","article-title":"Epithelial Ca2+ entry channels: transcellular Ca2+ transport and beyond","author":"Peng","year":"2003","journal-title":"J Physiol."},{"issue":"3","key":"2024020318404388800_bib10","doi-asserted-by":"crossref","first-page":"G618","DOI":"10.1152\/ajpgi.00269.2001","article-title":"Vitamin D-inducible calcium transport and gene expression in three Caco-2 cell lines","volume":"283","author":"Fleet","year":"2002","journal-title":"Am J Physiol Gastrointest Liver Physiol."},{"issue":"4","key":"2024020318404388800_bib11","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1073\/pnas.90.4.1345","article-title":"adaptation to dietary calcium phosphate deficiencies increase intestinal plasma membrane calcium pump gene expression","volume":"90","author":"Cai","year":"1993","journal-title":"Proc Natl Acad Sci U.S.A."},{"issue":"2","key":"2024020318404388800_bib12","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/0003-9861(80)90242-8","article-title":"Vitamin D-dependent calcium-binding protein synthesis by chick kidney and duodenal polysomes","volume":"203","author":"Christakos","year":"1980","journal-title":"Arch Biochem Biophys."},{"issue":"7","key":"2024020318404388800_bib13","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1359\/JBMR.040404","article-title":"Continuous parathyroid hormone induces cortical porosity in the rat: effects on bone turnover and mechanical properties","volume":"19","author":"Lotinun","year":"2004","journal-title":"J Bone Miner Res."},{"issue":"3","key":"2024020318404388800_bib14","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1677\/joe.1.06270","article-title":"Short-term continuous infusion of human parathyroid hormone. 1\u201334. fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL\/J6 mice","volume":"186","author":"Iida-Klein","year":"2005","journal-title":"J Endocrinol."},{"key":"2024020318404388800_bib15","doi-asserted-by":"crossref","first-page":"e1013","DOI":"10.1136\/bmj.e1013","article-title":"Diagnosis management of primary hyperparathyroidism","volume":"344","author":"Pallan","year":"2012","journal-title":"BMJ."},{"issue":"2","key":"2024020318404388800_bib16","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1097\/MAJ.0b013e31823bbb9b","article-title":"Normocalcemic primary hyperparathyroidism-characteristics and clinical significance of an emerging entity","volume":"343","author":"Shlapack","year":"2012","journal-title":"Am J Med Sci."},{"issue":"3","key":"2024020318404388800_bib17","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1017\/S0022215111002908","article-title":"Use of minimally invasive parathyroidectomy techniques in sporadic primary hyperparathyroidism: systematic review","volume":"126","author":"Gracie","year":"2012","journal-title":"J Laryngol Otol."},{"issue":"7","key":"2024020318404388800_bib18","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1001\/archsurg.1992.01420070095018","article-title":"Continuing evolution in the operative management of primary hyperparathyroidism","volume":"127","author":"Salti","year":"1992","journal-title":"Arch Surg."},{"issue":"11","key":"2024020318404388800_bib19","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.1210\/jc.2004-0294","article-title":"Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors","volume":"89","author":"Cetani","year":"2004","journal-title":"J Clin Endocrinol Metab."},{"issue":"3","key":"2024020318404388800_bib20","first-page":"449","article-title":"Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors","volume":"6","author":"Rosenberg","year":"1991","journal-title":"Oncogene."},{"issue":"5","key":"2024020318404388800_bib21","first-page":"1736","article-title":"Cyclin D1\/PRAD1 expression in parathyroid adenomas: an immunohistochemical study","volume":"81","author":"Hsi","year":"1996","journal-title":"J Clin Endocrinol Metab."},{"issue":"4","key":"2024020318404388800_bib22","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/ng0897-375","article-title":"Somatic mutation of the MEN1 gene in parathyroid tumours","volume":"16","author":"Heppner","year":"1997","journal-title":"Nat Genet."},{"issue":"27\u201328","key":"2024020318404388800_bib23","first-page":"400","article-title":"Age and gender distribution of primary hyperparathyroidism and incidence of surgical treatment in a European country with a particularly high life expectancy","volume":"139","author":"Richert","year":"2009","journal-title":"Swiss Med Wkly."},{"issue":"12","key":"2024020318404388800_bib24","first-page":"4789","article-title":"Parathyroid expression of calcium-sensing receptor protein and in vivo parathyroid hormone-Ca(2+) set-point in patients with primary hyperparathyroidism","volume":"85","author":"Cetani","year":"2000","journal-title":"J Clin Endocrinol Metab."},{"issue":"10","key":"2024020318404388800_bib25","first-page":"3481","article-title":"Tumor-specific decreased expression of calcium sensing receptor messenger ribonucleic acid in sporadic primary hyperparathyroidism","volume":"82","author":"Farnebo","year":"1997","journal-title":"J Clin Endocrinol Metab."},{"issue":"3","key":"2024020318404388800_bib26","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1677\/joe.0.1530437","article-title":"Ca2+ receptor mRNA and protein increase in the rat parathyroid gland with advancing age","volume":"153","author":"Autry","year":"1997","journal-title":"J Endocrinol."},{"issue":"(Suppl 1","key":"2024020318404388800_bib27","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.2215\/CJN.05910809","article-title":"Calcium metabolism in health and disease","author":"Peacock","year":"2010","journal-title":"Clin J Am Soc Nephrol."},{"issue":"2","key":"2024020318404388800_bib28","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1210\/jcem-58-2-223","article-title":"Age-related changes in parathyroid hormone and parathyroid hormone action in normal humans","volume":"58","author":"Marcus","year":"1984","journal-title":"J Clin Endocrinol Metab."},{"issue":"2","key":"2024020318404388800_bib29","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/jbmr.5650060205","article-title":"Interrelationship among vitamin D metabolism, true calcium absorption, parathyroid function, and age in women: evidence of an age-related intestinal resistance to 1,25-dihydroxyvitamin D action","volume":"6","author":"Eastell","year":"1991","journal-title":"J Bone Miner Res."},{"issue":"9","key":"2024020318404388800_bib30","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1172\/JCI10523","article-title":"Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice","volume":"107","author":"Imanishi","year":"2001","journal-title":"J Clin Invest."},{"issue":"4","key":"2024020318404388800_bib31","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/ng1295-389","article-title":"A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism [see comments]","volume":"11","author":"Ho","year":"1995","journal-title":"Nat Genet."},{"issue":"35","key":"2024020318404388800_bib32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/scisignal.1159945","article-title":"The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development","volume":"1","author":"Chang","year":"2008","journal-title":"Sci Signal."},{"issue":"1","key":"2024020318404388800_bib33","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1210\/me.2006-0110","article-title":"Parathyroid-specific double knockout of Gq and G11 alpha-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2+ -sensing receptor","volume":"21","author":"Wettschureck","year":"2007","journal-title":"Mol Endocrinol."},{"issue":"11","key":"2024020318404388800_bib34","doi-asserted-by":"crossref","first-page":"4597","DOI":"10.1210\/en.2005-0437","article-title":"Extracellular calcium and parathyroid hormone-related peptide signaling modulate the pace of growth plate chondrocyte differentiation","volume":"146","author":"Rodriguez","year":"2005","journal-title":"Endocrinology."},{"issue":"10","key":"2024020318404388800_bib35","doi-asserted-by":"crossref","first-page":"4984","DOI":"10.1210\/en.2007-0653","article-title":"Type B gammaaminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes","volume":"148","author":"Cheng","year":"2007","journal-title":"Endocrinology."},{"issue":"7","key":"2024020318404388800_bib36","doi-asserted-by":"crossref","first-page":"3156","DOI":"10.1210\/en.2007-0147","article-title":"Constitutive activity of the osteoblast Ca2+-sensing receptor promotes loss of cancellous bone","volume":"148","author":"Dvorak","year":"2007","journal-title":"Endocrinology."},{"issue":"12","key":"2024020318404388800_bib37","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1002\/jbmr.520","article-title":"Osteoblast extracellular Ca2+ -sensing receptor regulates bone development, mineralization, and turnover","volume":"26","author":"Dvorak-Ewell","year":"2011","journal-title":"J Bone Miner Res."},{"issue":"6","key":"2024020318404388800_bib38","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee","volume":"2","author":"Parfitt","year":"1987","journal-title":"J Bone Miner Res."},{"issue":"3","key":"2024020318404388800_bib39","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1210\/jcem-56-3-572","article-title":"Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue","volume":"56","author":"Brown","year":"1983","journal-title":"J Clin Endocrinol Metab."},{"issue":"6","key":"2024020318404388800_bib40","doi-asserted-by":"crossref","first-page":"F1177","DOI":"10.1152\/ajprenal.00038.2006","article-title":"Age-dependent alterations in Ca2+ homeostasis: role of TRPV5 and TRPV6","volume":"291","author":"van Abel","year":"2006","journal-title":"Am J Physiol Renal Physiol."},{"issue":"(Suppl 2","key":"2024020318404388800_bib41","doi-asserted-by":"crossref","first-page":"S121","DOI":"10.1002\/jbmr.5650061425","article-title":"Characterization and evaluation of asymptomatic primary hyperparathyroidism","author":"Bilezikian","year":"1991","journal-title":"J Bone Miner Res."},{"issue":"3","key":"2024020318404388800_bib42","first-page":"729","article-title":"Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism","volume":"80","author":"Silverberg","year":"1995","journal-title":"J Clin Endocrinol Metab."},{"issue":"1","key":"2024020318404388800_bib43","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/j.1365-2796.2004.01422.x","article-title":"Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features","volume":"257","author":"Bilezikian","year":"2005","journal-title":"J Intern Med."},{"issue":"1","key":"2024020318404388800_bib44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-2265.2007.03162.x","article-title":"Primary hyperparathyroidism and the skeleton","volume":"69","author":"Mosekilde","year":"2008","journal-title":"Clin Endocrinol (Oxf)."},{"issue":"3","key":"2024020318404388800_bib45","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.bone.2010.10.004","article-title":"Vitamin D deficiency influences histomorphometric features of bone in primary hyperparathyroidism","volume":"48","author":"Stein","year":"2011","journal-title":"Bone."},{"issue":"5","key":"2024020318404388800_bib46","doi-asserted-by":"crossref","first-page":"F1032","DOI":"10.1152\/ajprenal.00306.2002","article-title":"PTH increases renal 25(OH)D3-1alpha -hydroxylase (CYP1alpha) mRNA but not renal 1,25(OH)2D3 production in adult rats","volume":"284","author":"Armbrecht","year":"2003","journal-title":"Am J Physiol Renal Physiol."},{"issue":"6960","key":"2024020318404388800_bib47","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nature02040","article-title":"Osteoblastic cells regulate the haematopoietic stem cell niche","volume":"425","author":"Calvi","year":"2003","journal-title":"Nature."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.1846","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/28\/5\/1087\/56564572\/1846_ftp.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/28\/5\/1087\/56564572\/1846_ftp.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:48:33Z","timestamp":1710341313000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/28\/5\/1087-1100\/7598799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,12,13]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2012,12,13]]},"published-print":{"date-parts":[[2013,5,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.1846","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,5,1]]},"published":{"date-parts":[[2012,12,13]]}}}