title: Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice.
abstract: We studied mice with or without heterozygous deletion of the Casr in the parathyroid gland (PTG) [(PTG) CaSR(+/-)] to delineate effects of age and sex on manifestations of hyperparathyroidism (HPT). In control mice, aging induced a left-shift in the Ca(2+) /parathyroid hormone (PTH) set point accompanied by increased PTG CaSR expression along with lowered serum Ca(2+) and mildly increased PTH levels, suggesting adaptive responses of PTGs to aging-induced changes in mineral homeostasis. The aging effects on Ca(2+) /PTH set point and CaSR expression were significantly blunted in (PTG) CaSR(+/-) 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 Ca(2+) transport in kidney and intestine were unresponsive to the rising PTH levels. Such changes may promote negative Ca(2+) 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 (PTG) CaSR(+/-) mice, anabolic actions of the elevated PTH levels seemed to protect against trabecular bone loss at ≥ 3 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.
authors.affiliation: Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Nathan
authors.initials: N
authors.lastname: Liang
authors.forename: Tsui-Hua
authors.initials: TH
authors.lastname: Chen
authors.forename: Alfred
authors.initials: A
authors.lastname: Li
authors.forename: Christian
authors.initials: C
authors.lastname: Santa Maria
authors.forename: Michael
authors.initials: M
authors.lastname: You
authors.forename: Hanson
authors.initials: H
authors.lastname: Ho
authors.forename: Fuqing
authors.initials: F
authors.lastname: Song
authors.forename: Daniel
authors.initials: D
authors.lastname: Bikle
authors.forename: Chialing
authors.initials: C
authors.lastname: Tu
authors.forename: Dolores
authors.initials: D
authors.lastname: Shoback
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002908:Chronic Disease; D005260:Female; D006961:Hyperparathyroidism / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D012737:Sex Factors; D014057:Tomography, X-Ray Computed
chemical_list: D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D002118:Calcium