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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

Authors

  • 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
Background

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.

Methods

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

Results

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.

Conclusion

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.

Funding

  • NIDDK Support