Deficiency of SHP-1 protein-tyrosine phosphatase activity results in heightened osteoclast function and decreased bone density

Mice homozygous for the motheaten (Hcph(me)) or viable motheaten (Hcph(me-v )) mutations are deficient in functional SHP-1 protein-tyrosine phosphatase and show severe defects in hematopoiesis. Comparison of femurs from me(v)/ me(v) mice revealed significant decreases in bone mineral density (0.33 +/- 0.03 mg/mm(3) for me(v)/me(v) versus 0.41 +/- 0.01 mg/mm(3) for controls) and mineral content (1.97 +/- 0.36 mg for me(v)/me(v) versus 10.64 +/- 0.67 for controls) compared with littermate controls. Viable motheaten mice als o showed reduced amounts of trabecular bone and decreased cortical thicknes s. These bone abnormalities were associated with a 14% increase in numbers of multinucleated osteoclasts and an increase in osteoclast resorption acti vity. In co-cultures of normal osteoblasts with mutant or control bone marr ow cells, numbers of osteoclasts developing from mutant mice were increased compared with littermate control mice. Although me(v)/me(v) osteoclasts de velop in the absence of colony-stimulating factor (CSF)-1, nevertheless cul tured osteoclasts show increased size in the presence of CSF-1. CSF-1-defic ient osteopetrosis (op/op) mutant mice develop severe osteosclerosis. Howev er, doubly homozygous me(v)/me(v) op/op mice show an expansion of bone marr ow cavities and reduced trabecular bone mass compared with op/op mice. West ern blot analysis showed that several proteins that were markedly hyperphos phorylated on tyrosine residues were detected in the motheaten osteoclasts, including a novel 126-kd phosphotyrosine protein. The marked hyperphosphor ylation of a 126-kd protein In motheaten osteoclasts suggests that this pro tein depends on SHP-1 for dephosphorylation. These findings demonstrate tha t the decreased SHP-1 catalytic activity in me/me and me(v)/me(v) mice resu lts in an increased population of activated osteoclasts and consequent redu ction in bone density.