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Vav1 inhibits RANKL-induced osteoclast differentiation and bone resorption
Jin Sun Jang1,#, In Soon Kang1,#, Young-Nam Cha1, Zang Hee Lee2, Mary C Dinauer3, Young-June Kim4, Chaekyun Kim1,*
1Department of Pharmacology, School of Medicine, Inha University,
2Department of Cell and Developmental Biology, School of Dentistry, Seoul National University,
3Department of Pediatrics, Washington University,
4Department of Microbiology and Immunology, Indiana University
Abstract
Vav1 is a Rho/Rac guanine nucleotide exchange factor primarily expressed in hematopoietic cells. In this study, we investigated the potential role of Vav1 in osteoclast (OC) differentiation by comparing the ability of bone marrow mononuclear cells (BMMCs) obtained from Vav1-deficient (Vav1-/-) and wild-type (WT) mice to differentiate into mature OCs upon stimulation with macrophage colony stimulating factor and receptor activator of nuclear kappa B ligand in vitro. Our results suggested that Vav1 deficiency promoted the differentiation of BMMCs into OCs, as indicated by the increased expression of tartrate-resistant acid phosphatase, cathepsin K, and calcitonin receptor. Therefore, Vav1 may play a negative role in OC differentiation. This hypothesis was supported by the observation of more OCs in the femurs of Vav1-/- mice than in WT mice. Furthermore, the bone status of Vav1-/- mice was analyzed in situ and the femurs of Vav1-/- mice appeared abnormal, with poor bone density and fewer number of trabeculae. In addition, Vav1-deficient OCs showed stronger adhesion to vitronectin, an メvモ3 integrin ligand important in bone resorption. Thus, Vav1 may inhibit OC differentiation and protect against bone resorption.
Abstract, Accepted Manuscript(in press) [Submitted on January 7, 2019, Accepted on April 24, 2019]
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