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

Naturally occuring inactivating mutations of the Src homology 2 (SH2) domai n-containing tyrosine phosphatase 1 (SHP-1) in mice give rise to the mothea ten (me) phenotype, me/me mice have multiple hematopoietic abnormalities, s uggesting that this phosphatase plays an important role in hematopoiesis. S HP-1 binds to and is activated by several hematopoietic surface receptors, including the colony-stimulating factor type 1 receptor. We have examined t he role of SHP-1 in osteoclastogenesis and osteoclast function using mice w ith the viable motheaten (me(nu)/me(nu) ) mutation, which has markedly decr eased 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 (OCL s) in cocultures of me(nu)/me(nu) hematopoietic cells with normal osteoblas ts was significantly increased. In contrast, the number of OCLs formed in t he 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 incre ased. 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 th e function of osteoclasts. (C) 1999 by Elsevier Science Inc. All rights res erved.