contributed equally to this work.
Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: parathyroid hormone (PTH); 1,25-dihydroxycholecalciferol (1,25-(OH)2D3); transient receptor potential (TRP); TRP cation channel subfamily V, member 5 (TRPV5); TRP cation channel subfamily V, member 6 (TRPV6); last loop of proximal tubules (LPT); hypoxanthine-guanine phosphoribosyl transferase (HPRT); bone volume (BV); total bone marrow volume including trabeculae (TV); trabecular bone volume fraction (BV/TV); trabecular thickness (Tb.Th); trabecular number (Tb.N); connectivity density (CD); structure model index (SMI); cortical volume (Ct.V); endocortical volume (Ec.V); total diaphyseal volume (Dp.V), cortical thickness (Ct.Th); cortical bone volume fraction (Ct.V/Dp.V); moment of inertia (MOI); Tartrate-resistant acid phosphatase (TRAP); number of osteoclasts per bone surface area (N.Oc/BS); surface area of osteoclasts per bone surface area (Oc.S/BS); arginine vasopressin (AVP); Na + -Ca 2+ exchanger (NCX1); vitamin D receptor (VDR).
IntroductionCa 2+ is the most abundant cation in the human body and serves a number of important physiological functions, including fertilization, synaptic transmission, muscle contraction, blood clotting, and bone mineralization. The extracellular Ca 2+ concentration is controlled by the kidney, intestine, and bone through the action of the calciotropic hormones, including parathyroid hormone (PTH) and 1,25-dihydroxycholecalciferol (1,25-(OH) 2 D 3 ). In humans, the daily dietary Ca 2+ intake is less than 1,000 mg, of which only 30% is absorbed in the intestinal tract. This percentage is significantly enhanced during growth, pregnancy, and lactation by increased levels of circulating 1,25-(OH) 2 D 3 . Although there is continuous turnover of bone mass, there is no net gain or loss of Ca 2+ from bone in a young and healthy individual. This indicates that healthy adults excrete a maximum of 300 mg Ca 2+ in the urine to balance the intestinal Ca 2+ uptake and that the remaining 98% of the Ca 2+ filtered in the glomeruli is reabsorbed along the nephron. The molecular mechanism responsible for Ca 2+ absorption in the small intestine and the kidney was elusive for a long time.Renal Ca 2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 Ca 2+ ions play a fundamental role in many cellular processes, and the extracellular concentration of Ca 2+ is kept under strict control to allow the proper physiological functions to take place. The kidney, small intestine, and bone determine the Ca 2+ flux to the extracellular Ca 2+ pool in a concerted fashion. Transient receptor potential (TRP) cation channel subfamily V, members 5 and 6 (TRPV5 and TRPV6) have recently been postulated to be the molecular gatekeepers facilitating Ca 2+ influx in these tissues and are members of the TRP family, which mediates diverse biological effects ranging from pain perception to male aggression. Genetic ablation of TRPV5 in the mouse allowed u...