ECTS Abstracts (2015) 1 P400

Maternal TRPV6 is Crucial for Bone Development

Bram van der Eerden1, Marijke Schreuders-Koedam1, Cindy van der Leije1, Marc Freichel3, Johannes van Leeuwen1, Veit Flockerzi2 & Petra Weissgerber2

1Erasmus MC, Internal Medicine, Rotterdam, The Netherlands; 2Insitute for Pharmacology and Toxicology, University of Saarland, Homburg, Germany; 3Pharmacological Insitute, University of Heidelberg, Heidelberg, Germany.

Calcium is essential for many physiological processes, including cell signalling, nerve excitation, but also skeletal mineralisation. Despite expression of the calcium channel TRPV6 in bone cells, young mice defective for the calcium-transporting pore region of TRPV6 (TRPV6D541A) do not develop a bone phenotype. Since TRPV6 is highly expressed in the placenta, we assessed whether placental TRPV6 deficiency, known to disturb calcium homeostasis in foetal development, affects bone development. Besides, we assessed the effect of low calcium diets on bone development of these mice. Homozygous TRPV6D541A mothers that are TRPV6 deficient were crossed with heterozygous fathers, yielding male homozygous TRPV6D541A offspring. Directly after weaning, they were put on a normal (1% w/w) or low (0.2% w/w) calcium diet for 6 weeks. Bone microarchitecture and strength were assessed at 9 weeks, using microCT and 3-point bending tests. TRPV6D541A offspring from homozygous mothers displayed reduced cortical bone mass when compared with wildtype mice (cortical volume (Ct.V),-15%, perimeter,-10%, moment of inertia (MOI),-30%). When these mice were put on a low calcium diet, both trabecular (BV/TV,-50%, trabecular thickness (,-25%, Tb.N,-40%) and cortical (Ct.V,-40%, perimeter,-20%, MOI,-60%) bone mass were severely diminished along with compromised bone strength (work-to-failure,-50%) and reduced mineral bone formation rate (MAR and BFR,-65%) as assessed by histomorphometry. TRPV6D541A offspring from heterozygous mothers (exposed to one functional placental TRPV6 allele) on a low calcium (0.2% w/w) diet had reduced cortical bone mass compared to wildtype littermates (Ct.V,-20%, perimeter,-10%, MOI,-30%). The current study demonstrated that placental TPRV6 is essential for normal cortical bone development. Additional comparative neonatal calcium diet studies with homozygous and heterozygous TRPV6 deficient offspring uncovered that TRPV6 is critical for proper trabecular bone formation and to limit detrimental effects of low calcium on cortical bone. Overall, this study demonstrates the importance of TRPV6 for bone in case of low calcium stress.

Disclosure: The authors declared no competing interests.

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