Proliferation and differentiation of osteoblasts in osteopetrotic rats: modification in expression of genes encoding cell growth and extracellular matrix proteins.

Osteopetrosis is characterized by a congenital defect in osteoclast differentiation and/or activity. The unresorbed matrix produces dense and sclerotic bone with the absence of a marrow cavity. Osteoblasts function in both the production and degradation of bone. However, the potential contribution of an osteoblast abnormality in the etiology of osteopetrosis has not been explored. We examined expression of cell growth-related genes (Core Hl histones and c myc) and genes related to osteoblast differentiation (Type I collagen, osteopontin and osteocalcin, an osteoblast-specific marker) in calvarial bone from the 3 osteopetrotic mutations in the rat (ia/ia, op/op and tl/tl) and normal littermates. mRNA preparations from these bones showed up to a 5-fold increase in all cell growth related genes in tl/tl and op/op rats, compared to normal littermates, suggesting a stimulation of proliferative activity of bone cells. The matrix genes also exhibited 2 to 10+fold increases in these two mutations. In contrast ia/ia rats showed no significant changes in expression of proliferation or matrix genes (except for osteopontin) which is consistent with the greatly reduced skeletal sclerosis in this mutation at the time (4 wk) when tissues were analyzed. Since the tl and op mutations have greater elevations in serum 1,25(OH)2D3 than found in the ia mutation, these results may reflect a stimulatory effect on cell proliferation and osteoblast activity by 1,25(OH)2D3. These data suggest that, in addition to osteoclast abnormalities, certain osteopetroses may also have aberrations of osteoblast function.