Activation of TRPV4 promotes osteoclasts differentiation

Excerpt

Osteoclast differentiation is critically dependent on cellular calcium (Ca²⁺) signaling. Intracellular Ca²⁺ concentration ([Ca²⁺]_i) is regulated by two flux pathways; Ca²⁺ oscillations evoked by the release of Ca²⁺ from the endoplasmic reticulum, and/or Ca²⁺ entry from the extracellular fluid. The latter is carried out by the plasmamembrane localized Ca²⁺ permeable channel such as "transient receptor potentials (Trps)". Trpv4-deficient mice show an increased bone mass due to impaired osteoclast maturation, because Trpv4 mediates Ca²⁺ influx at the late stage of osteoclast differentiation and hereby regulates Ca²⁺ signaling [1]. Furthermore, substitutions of amino acids R616Q/V620I of Trpv4 have been discovered as gain of function mutations resulting in increased Ca²⁺ transport [2]. Since the region of these substitutions at the trans-membrane pore domain is perfectly conserved between species, we created a mutant of the mouse Trpv4 (Trpv4^R616Q/V620I) and characterized it on Ca²⁺ signaling especially in the occurrences of oscillations at the initial step of osteoclast differentiation. …