Lifelong challenge of calcium homeostasis in male mice lacking TRPV5 leads to changes in bone and calcium metabolism

Abstract

Trpv5 plays an important role in calcium (Ca2+) homeostasis, among others by mediating renal calcium reabsorption. Accordingly, Trpv5 deficiency strongly stresses Ca2+ homeostasis in order to maintain stable serum Ca2+. We addressed the impact of lifelong challenge of calcium homeostasis on the bone phenotype of these mice.Aging significantly increased serum 1,25(OH)2D3 and PTH levels in both genotypes but they were more elevated in Trpv5−/− mice, whereas serum Ca2+ was not affected by age or genotype. Age-related changes in trabecular and cortical bone mass were accelerated in Trpv5−/− mice, including reduced trabecular and cortical bone thickness as well as reduced bone mineralization. No effect of Trpv5 deficiency on bone strength was observed. In 78-week-old mice no differences were observed between the genotypes regarding urinary deoxypyridinoline, osteoclast number, differentiation and activity as well as osteoclast precursor numbers, as assessed by flow cytometry.In conclusion, life-long challenge of Ca2+ homeostasis present in Trpv5−/− mice causes accelerated bone aging and a low cortical and trabecular bone mass phenotype. The phenotype of the Trpv5−/− mice suggests that maintenance of adequate circulatory Ca2+ levels in patients with disturbances in Ca2+ homeostasis should be a priority in order to prevent bone loss at older age.

Effects and mechanisms of microenvironmental acidosis on osteoclast biology

“…This means that bone loss should be attributed to 1,25(OH) 2 D 3 , rather than TRPV5 deletion, in vivo. Especially, in long-term bred TRPV5-deficient mice, old TRPV5-deficient mice bone resorption function was found to be essentially the same as that of wild mice, which is attributed to over expression of 1,25(OH) 2 D 3 in old mice compared to young ones (58). In short, this evidence has confirmed that TRPV5 promotes bone resorption in wild type mice (57,58,60,61).…”

“…However, the effects of TRPV5 on bone resorption by osteoclasts have not been conclusively determined. TRPV5-deficient mice showed gross phenotypic dysregulation of Ca 2+ homeostasis, severe hypercalciuria and excess bone loss in the musculoskeletal system (57)(58)(59). Interestingly, bone resorption was significantly inhibited in in vitro cell cultures from TRPV5-deficient mice (57,58,60).…”

“…TRPV5-deficient mice showed gross phenotypic dysregulation of Ca 2+ homeostasis, severe hypercalciuria and excess bone loss in the musculoskeletal system (57)(58)(59). Interestingly, bone resorption was significantly inhibited in in vitro cell cultures from TRPV5-deficient mice (57,58,60). Apparently, contradictory phenotypes of reduced bone resorption and excessive bone loss concurrently appearing in the same mice are inconsistent.…”

“…This implies that, in vivo, TRPV5-deficient mice have bone resorption compensatory mechanisms. 1,25(OH) 2 D 3 and TRPV6, as potential candidates, may contribute to this mechanism (57,58,60). 1,25(OH) 2 D 3 is a powerful regulator that maintains Ca 2+ homeostasis and compensates for the loss of Ca 2+ in the absence of TRPV5, but at the expense of enhanced bone resorption (57).…”

Calcium-Permeable Channels Cooperation for Rheumatoid Arthritis: Therapeutic Opportunities

“…This suggests that TRPV5 may be an important pathway, mediating RANKL-induced [Ca 2+ ] i elevation in osteoclasts. A role for TRPV5 in osteoclast calcium homeostasis was also confirmed [ 128 ]. Interestingly, studies have shown that estrogen inhibits RANKL-induced osteoclast differentiation and bone resorption activity by increasing the expression of TRPV5 channels [ 129 ].…”