Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis

Abstract

Energy-dependent intestinal calcium absorption is important for the maintenance of calcium and bone homeostasis, especially when dietary calcium supply is restricted. The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a crucial regulator of this process and increases the expression of the transient receptor potential vanilloid 6 (Trpv6) calcium channel that mediates calcium transfer across the intestinal apical membrane. Genetic inactivation of Trpv6 in mice (Trpv6−/−) showed, however, that TRPV6 is redundant for intestinal calcium absorption when dietary calcium content is normal/high and passive diffusion likely contributes to maintain normal serum calcium levels. At the other hand, Trpv6 inactivation impaired the increase in intestinal calcium transport following calcium restriction, however without resulting in hypocalcemia. A possible explanation is that normocalcemia is maintained at the expense of bone homeostasis, a hypothesis investigated in this study. In this study, we thoroughly analyzed the bone phenotype of Trpv6−/− mice receiving a normal (~ 1%) or low (~ 0.02%) calcium diet from weaning onwards using micro-computed tomography, histomorphometry and serum parameters. When dietary supply of calcium is normal, Trpv6 inactivation did not affect growth plate morphology, bone mass and remodeling parameters in young adult or ageing mice. Restricting dietary calcium had no effect on serum calcium levels and resulted in a comparable reduction in bone mass accrual in Trpv6+/+ and Trpv6−/− mice (−35% and 45% respectively). This decrease in bone mass was associated with a similar increase in bone resorption, whereas serum osteocalcin levels and the amount of unmineralized bone matrix were only significantly increased in Trpv6−/− mice. Taken together, our findings indicate that TRPV6 contributes to intestinal calcium transport when dietary calcium supply is limited and in this condition indirectly regulates bone formation and/or mineralization.

Increased biological response to 1,25(OH)2D3in genetic hypercalciuric stone-forming rats

“…While expression of TRPV5 is limited to kidney (41) and mouse testis (49), a second apical Ca transporter, TRPV6, is found in multiple tissues (49,93) with highest kidney expression in TALH (75). While the apical distribution of renal TRPV6 and its known role in intestinal Ca absorption (66,95) is consistent with renal tubular Ca reabsorption, direct evidence is lacking.…”

“…However, hypercalciuria in TRPV6 Ϫ/Ϫ mice may be a result of secondary hyperparathyroidism (11) and not a primary defect in renal Ca reabsorption. While neither TRPV6 nor calbindin D 9K are required for 1,25D-stimulated intestinal Ca transport in mice (8, 55) on a Ca-restricted diet, TRPV6 Ϫ/Ϫ mice exhibit greater bone resorption (66), suggesting that TRPV6 is important to maintain normal Ca balance. Knockin of a mutated TRPV6 incapable of Ca permeation led to impaired intestinal Ca uptake with a limited Ca diet (95).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…More strikingly, TRPV6 contributes to intestinal calcium transport only under conditions when the dietary calcium supply is limited. In such situations, TRPV6 regulates bone formation and mineralization (Lieben et al, 2010). TRPV6 controls the extracellular Ca 2+ concentration toward the distal segments of the epididymal duct, which is essential for survival of spermatozoa.…”

Knockout of TRPV6 Causes Osteopenia in Mice by Increasing Osteoclastic Differentiation and Activity

“…Histology and histomorphometry were performed as described previously [24] . Left tibiae were fixed in Burkhardt's solution, embedded undecalcified in methyl methacrylate, and sectioned at 4 μm.…”