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This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Poster presentation

Activation of TRPV4 promotes osteoclasts differentiation

Ritsuko Masuyama

  • Correspondence: Ritsuko Masuyama

Author Affiliations

Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Arthritis Research & Therapy 2012, 14(Suppl 1):P42  doi:10.1186/ar3643

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S1/P42


Published:9 February 2012

© 2012 Masuyama; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Poster presentation

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 (Trpv4R616Q/V620I) and characterized it on Ca2+ signaling especially in the occurrences of oscillations at the initial step of osteoclast differentiation.

Intact Trpv4 and Trpv4R616Q/V620I were equally transduced by retroviral infection into bone marrow derived hematopoietic cells isolated from WT mice, and mock-transfection was used as control. The resorptive activity was significantly increased in Trpv4R616Q/V620I-expressing osteoclasts when treated with RANKL for 7 days, associating increased NFATc1 and calcitonin receptor mRNA expression. Noteworthy, the expression of these differentiation markers was already elevated in Trpv4R616Q/V620I cells before RANKL treatment, suggesting that the activation of Trpv4 advances osteoclast differentiation through Ca2+-NFATc1 pathway. Accordingly, basal [Ca2+]i, analyzed in progenitor cells treated with RANKL for 24 hr, increased 2 fold in intact Trpv4 (p < 0.05) and 3 fold in Trpv4R616Q/V620I (p < 0.01) compared to controls. Although spontaneous Ca2+ oscillations were absent in control progenitor cells, Trpv4R616Q/V620I progenitor cells already displayed irregular oscillatory pattern.

In summary, our findings provide evidences that the activation of Ca2+ permeable channel supports Ca2+ oscillations in progenitor cells and therefore promotes the potential of osteoclast differentiation.

References

  1. Masuyama R, Vriens J, Voets T, Karashima Y, Owsianik G, Vennekens R, Lieben L, Torrekens S, Moermans K, Vanden Bosch A, et al.: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.

    Cell Metab 2008, 8:257-265. PubMed Abstract | Publisher Full Text OpenURL

  2. Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B, Nelson SF, Lachman RS, Wilcox WR, Reyno S, Quadrelli R, et al.: Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.

    Nat Genet 2008, 40:999-1003. PubMed Abstract | Publisher Full Text OpenURL