The tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity:: Increased resorption and osteopenia in mev/mev mutant mice
The tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity:: Increased resorption and osteopenia in mev/mev mutant mice
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DOI：
10.1016/s8756-3282(99)00174-x
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发表时间：
1999-09-01
期刊：
影响因子：
4.1
通讯作者：
Baron, R
中科院分区：
文献类型：
--
作者：
Aoki, K;Didomenico, E;Baron, R
含Src同源2（SH 2）结构域的酪氨酸磷酸酶1（SHP-1）在小鼠中的自然失活突变引起蛾化（me）表型，me/me小鼠具有多种造血异常，表明该磷酸酶在造血中起重要作用。SHP-1与几种造血表面受体结合并被其激活，包括集落刺激因子1型受体。我们已经研究了SHP-1在破骨细胞生成和破骨细胞功能中的作用，使用具有活的motheaten（me（nu）/me（nu））突变的小鼠，其显著降低了SHP-1活性。6周龄me（nu）/me（nu）小鼠和对照同窝小鼠的组织形态计量学分析显示，骨吸收指数增加，骨量减少。在me（nu）/me（nu）造血细胞与正常成骨细胞共培养中形成的破骨细胞样细胞（OCL）的数量显著增加。相反，在正常骨髓细胞与me（nu）/me（nu）成骨细胞的共培养中形成的OCL的数量与对照组没有显著差异。me（nu）/me（nu）OCL和真正的破骨细胞的骨吸收活性也被发现增加。最后，来自me（nu）/me（nu）和对照OCL的蛋白质的蛋白质印迹揭示了me（nu）/me（nu）裂解物中酪氨酸磷酸化的总体增加。这些在体内和体外的结果表明，SHP-1是骨吸收的负调节剂，影响破骨细胞的形成和功能。(C)1999年，Elsevier Science Inc. All rights reserved.
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.