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Title: SH3BP2 is an activator of NFAT activity and osteoclastogenesis

Abstract

Heterozygous activating mutations in exon 9 of SH3BP2 have been found in most patients with cherubism, an unusual genetic syndrome characterized by excessive remodeling of the mandible and maxilla due to spontaneous and excessive osteoclastic bone resorption. Osteoclasts differentiate after binding of sRANKL to RANK induces a number of downstream signaling effects, including activation of the calcineurin/NFAT (nuclear factor of activated T cells) pathway. Here, we have investigated the functional significance of SH3BP2 protein on osteoclastogenesis in the presence of sRANKL. Our results indicate that SH3BP2 both increases nuclear NFATc1 in sRANKL treated RAW 264.7 preosteoclast cells and enhances expression of tartrate resistant acid phosphatase (TRAP), a specific marker of osteoclast differentiation. Moreover, overexpression of SH3BP2 in RAW 264.7 cells potentiates sRANKL-stimulated phosphorylation of PLC{gamma}1 and 2, thus providing a mechanistic pathway for the rapid translocation of NFATc1 into the nucleus and increased osteoclastogenesis in cherubism.

Authors:
 [1];  [2];  [1];  [3];  [4]
  1. Department of Orthopaedic Surgery, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 (United States)
  2. (United States), E-mail: lietmas@ccf.org
  3. (United States)
  4. The Division of Endocrinology, The Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104 (United States)
Publication Date:
OSTI Identifier:
21143747
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 371; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2008.04.080; PII: S0006-291X(08)00733-X; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACID PHOSPHATASE; JAW; MUTATIONS; PATIENTS; PEDIATRICS; PHOSPHORYLATION; SIMULATION; TEETH; TRANSLOCATION

Citation Formats

Lietman, Steven A., Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH 44195, Yin Lihong, Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH 44195, and Levine, Michael A. SH3BP2 is an activator of NFAT activity and osteoclastogenesis. United States: N. p., 2008. Web. doi:10.1016/j.bbrc.2008.04.080.
Lietman, Steven A., Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH 44195, Yin Lihong, Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH 44195, & Levine, Michael A. SH3BP2 is an activator of NFAT activity and osteoclastogenesis. United States. doi:10.1016/j.bbrc.2008.04.080.
Lietman, Steven A., Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH 44195, Yin Lihong, Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH 44195, and Levine, Michael A. 2008. "SH3BP2 is an activator of NFAT activity and osteoclastogenesis". United States. doi:10.1016/j.bbrc.2008.04.080.
@article{osti_21143747,
title = {SH3BP2 is an activator of NFAT activity and osteoclastogenesis},
author = {Lietman, Steven A. and Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH 44195 and Yin Lihong and Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH 44195 and Levine, Michael A.},
abstractNote = {Heterozygous activating mutations in exon 9 of SH3BP2 have been found in most patients with cherubism, an unusual genetic syndrome characterized by excessive remodeling of the mandible and maxilla due to spontaneous and excessive osteoclastic bone resorption. Osteoclasts differentiate after binding of sRANKL to RANK induces a number of downstream signaling effects, including activation of the calcineurin/NFAT (nuclear factor of activated T cells) pathway. Here, we have investigated the functional significance of SH3BP2 protein on osteoclastogenesis in the presence of sRANKL. Our results indicate that SH3BP2 both increases nuclear NFATc1 in sRANKL treated RAW 264.7 preosteoclast cells and enhances expression of tartrate resistant acid phosphatase (TRAP), a specific marker of osteoclast differentiation. Moreover, overexpression of SH3BP2 in RAW 264.7 cells potentiates sRANKL-stimulated phosphorylation of PLC{gamma}1 and 2, thus providing a mechanistic pathway for the rapid translocation of NFATc1 into the nucleus and increased osteoclastogenesis in cherubism.},
doi = {10.1016/j.bbrc.2008.04.080},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 371,
place = {United States},
year = 2008,
month = 7
}
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