ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: FR-PO480

Role of Reduced [Ca2+]i in the Denser Bone Phenotype of Mouse Familial Hypocalciuric Hypercalcemia (FHH) Induced by Deleting the Gene Encoding Canonical Transient Receptor Potential 1 (TRPC 1) Channel

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic


  • Eby, Bonnie, University of Oklahoma Heath Sciences Center, Oklahoma City, Oklahoma, United States
  • Onopiuk, Marta, OUHSC, Oklahoma City, Oklahoma, United States
  • Humphrey, Marybeth, University of Oklahoma, Oklahoma City, Oklahoma, United States
  • Tsiokas, Leonidas, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Lau, Kai, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States

In reporting the 80% increased bone mass in FHH, we noted +/- mice have similar hypercalcemia (11 vs 10.7 mg %), calcitriol, & calcitonin as null, but no hyperparathyroidism (HPT) or hypocalciuria. We asked if gene dosage causes these & the bone phenotype. In parathyroid gland (PTG), renal cells & osteocytes from null mice, we found lower [Ca2+]i & blunted response to CaSR agonists, shifting right Ca set point for PTH release. We tested the hypothesis that reduced [Ca2+]i alters secretion of cytokines & phosphatonins to produce greater renal Ca & P retention & more bone mineral accretion.


We did metabolic studies in ♂ littermates of all 3 genotypes & measured blood chemistry as published & cytokines by mouse ELISA.


At 6.5 mon, plasma leptin in null (2.34), but not +/- (1.78), was 75% higher than wild-type (wt) (1.3 ng/ml), compatible with known increased leptin secretion by low [Ca2+]i in adipocytes. Given published positive feedback between PTH by PTG & leptin by adipocytes, the data suggest leptin could aggravate the HPT in null mice. Plasma adiponectin was reduced in null (5.36 vs 6.17 in +/- vs 6.39 µg/ml in wt), consistent with its known inhibition by low [Ca2+]i & with the published hypocalciuric effects if downregulated. Indeed, despite hypercalcemia, urine Ca (50 in null vs 79 in +/- vs 84 µg/d in wt) & Ca clearance (0.68 vs 1.08 vs 1.25 µl/min) were lower in null. Consistent with the low [Ca2+]i we found in osteocytes, FGF-23 was down in null (51% at 4 mon & 32 % by 5 mon). At 8 mon, P clearance was reduced in null (48 vs 60 in +/- vs 67 µl/min in wt). Thus, serum P was elevated in null (7.4 vs. 6.2 in +/- vs 6.3 mg % in wt). At 12 mon, urine P stayed 50% lower in null, consistent with the anti-phosphaturia of reduced FGF-23.


Our data support this model of bone phenotype in null mice. 1. Disturbed [Ca2+]i homeostasis from losing both alleles shifts Ca set point to cause HPT. 2. Reduced [Ca2+]i in adipocytes triggers leptin, aggravates HPT, & inhibits adiponectin. 3. Reduced [Ca2+]i in osteocytes inhibits FGF-23. 4. In concert, these hypocalciuric & anti-phophaturic factors promote renal Ca & P retention to favor bone formation, independent of any other renal & skeletal effects of TRPC1 deficiency.


  • NIDDK Support