Calcium (Ca²⁺) homeostasis is tightly regulated by the coordinated actions of the intestine, kidneys and bone. Ca²⁺ transport occurs via either a paracellular pathway, which depends on the expression of select claudins, including claudin-12 (CLDN12) in the tight junction, or a transcellular pathway, involving apical influx through TRPV6. While disruption of paracellular or transcellular pathways impairs transepithelial Ca²⁺ flux, Cldn12 -deficient mice and Trpv6 mutant ( Trpv6 D541A/D541A ) mice do not display alterations in Ca²⁺ balance as reported previously, perhaps because one pathway compensates for the other. To test this hypothesis, we generated a double knockout mouse (DKO, Cldn12 -/- / Trpv6 D541A/D541A ) to assess Ca²⁺ homeostasis using metabolic cage balance studies, quantitative real-time PCR, and micro-computed tomography (Micro-CT). Despite lacking these key Ca²⁺ transport mechanisms, DKO mice maintained normal blood Ca²⁺. However, PTH and calcitriol were significantly elevated, as were renal Cyp27b1 and Cyp24a1 expression, consistent with hormonal compensation. The proximal colon and cecum exhibited significant compensatory changes in Ca²⁺-regulatory gene expression, including upregulation of the Ca²⁺ buffer S100g and basolateral extrusion mechanism Atp2b1. Notably, the Ca²⁺ channel Trpv5 , which is absent from the intestine, became detectable in the proximal colon and cecum, but not in the distal colon or small intestine of DKO mice. Micro-CT of bone revealed reduced trabecular bone volume and thickness, indicating increased bone resorption as a secondary compensatory mechanism. This study highlights the adaptive plasticity of Ca²⁺-regulatory mechanisms and suggests a role for TRPV5 in reabsorbing Ca²⁺ from the proximal colon and cecum when upstream mechanisms of Ca²⁺ absorption are impaired. deletion of both Cldn12 and Trpv6 in mice disrupts Ca²⁺ homeostasis revealing compensatory mechanisms. These include increased expression of Trpv5 , Trpv6 , S100g (Calbindin-D 9K ) and Atp2b1 (PMCA1b) in the proximal colon and cecum, as well as upregulation of Cacna1d (Cav1.3) in the jejunum, normalizing intestinal Ca²⁺ absorption in the absence of Trpv6 and Cldn12 . In addition, bone remodeling contributes to the maintenance of normal serum Ca²⁺ levels. Renal compensation appears limited, despite elevated PTH, which increases Cyp27b1 expression stimulating the conversion of 25(OH)D to 1,25(OH)₂D. Adapted from Servier Medical Art ( https://smart.servier.com ), licensed under CC BY 4.0 ( https://creativecommons.org/licenses/by/4.0/ ). • Loss of Cldn12 and Trpv6 does not induce hypocalcemia in mice. However, increased PTH and calcitriol mediates hormonal compensation. • In Cldn12 and Trpv6 knockout mice there is evidence of increased transcellular calcium absorption and in the colon, this appears to be through Trpv5. This novel intestinal pathway likely helps maintain blood calcium levels. • Despite intestinal compensation, skeletal mineralization remains inadequate, likely due to bone resorption resulting in decreased bone mineral density.
Deluque et al. (Wed,) studied this question.