The tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity:: Increased resorption and osteopenia in mev/mev mutant mice

被引:91
作者
Aoki, K
Didomenico, E
Sims, NA
Mukhopadhyay, K
Neff, L
Houghton, A
Amling, M
Levy, JB
Horne, WC
Baron, R
机构
[1] Yale Univ, Sch Med, Dept Orthopaed, New Haven, CT 06510 USA
[2] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA
[3] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06510 USA
关键词
Src homology 2-domain-containing tyrosine phosphatase 1(SHP-1); motheaten; osteopenia; osteoclastogenesis; osteoclast function;
D O I
10.1016/S8756-3282(99)00174-X
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Naturally occuring inactivating mutations of the Src homology 2 (SH2) domain-containing tyrosine phosphatase 1 (SHP-1) in mice give rise to the motheaten (me) phenotype, me/me mice have multiple hematopoietic abnormalities, suggesting that this phosphatase plays an important role in hematopoiesis. SHP-1 binds to and is activated by several hematopoietic surface receptors, including the colony-stimulating factor type 1 receptor. We have examined the role of SHP-1 in osteoclastogenesis and osteoclast function using mice with the viable motheaten (me(nu)/me(nu) ) mutation, which has markedly decreased SHP-1 activity. Histomorphometric analysis of 6-week-old me(nu)/me(nu) mice and control littermates showed a marked osteopenia with an increase in bone resorption indices. The number of formed osteoclast-like cells (OCLs) in cocultures of me(nu)/me(nu) hematopoietic cells with normal osteoblasts was significantly increased. In contrast, the number of OCLs formed in the coculture of normal bone marrow cells with the me(nu)/me(nu) osteoblasts was not significantly different from controls. The bone-resorbing activity of me(nu)/me(nu) OCLs and authentic osteoclasts was also found to be increased. Finally, Western blotting of proteins from me(nu)/me(nu) and control OCLs revealed an overall increase in tyrosine phosphorylation in the me(nu)/me(nu) lysates. These in vivo and in vitro results suggest that SHP-1 is a negative regulator of bone resorption, affecting both the formation and the function of osteoclasts. (C) 1999 by Elsevier Science Inc. All rights reserved.
引用
收藏
页码:261 / 267
页数:7
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