Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice

Authors

  • Zhiqiang Cheng,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Nathan Liang,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Tsui-Hua Chen,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Alfred Li,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Christian Santa Maria,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Michael You,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Hanson Ho,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Fuqing Song,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Daniel Bikle,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Chialing Tu,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Dolores Shoback,

    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
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  • Wenhan Chang

    Corresponding author
    1. Endocrine Research Unit, Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, CA, USA
    • Endocrine Research Unit, 111N, San Francisco Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA.
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Abstract

We studied mice with or without heterozygous deletion of the Casr in the parathyroid gland (PTG) [PTGCaSR(+/–)] 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(+/–) 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(+/–) 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. © 2013 American Society for Bone and Mineral Research.

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