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) 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(v)/me(v)) mutation, which has markedly decreased SHP-1 activity. Histomorphometric analysis of 6-week-old me(v)/me(v) 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(v)/me(v) 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(v)/me(v) osteoblasts was not significantly different from controls. The bone-resorbing activity of me(v)me(v) OCLs and authentic osteoclasts was also found to be increased. Finally, Western blotting of proteins from me(v)/me(v) and control OCLs revealed an overall increase in tyrosine phosphorylation in the me(v)/me(v) 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.
Aoki
K
K
Department of Orthopaedics, and Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
Didomenico
E
E
Sims
N A
NA
Mukhopadhyay
K
K
Neff
L
L
Houghton
A
A
Amling
M
M
Levy
J B
JB
Horne
W C
WC
Baron
R
R
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001851:Bone Diseases, Metabolic / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000201:enzymology; D001862:Bone Resorption / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010010:Osteoclasts / Q000201:enzymology / Q000378:metabolism*; D054645:Protein Phosphatase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D012886:Skull / Q000166:cytology / Q000201:enzymology; D013154:Spleen / Q000166:cytology; D013977:Tibia / Q000254:growth & development / Q000473:pathology; D018909:src Homology Domains / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D054645:Protein Phosphatase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases