Osteopetrosis in the rat: coexistence of reductions in osteocalcin and bone resorption

Osteocalcin, one of the vitamin K-dependent bone proteins, has recently been implicated in bone resorption. To explore this hypothesis, bone and serum osteocalcin were measured in three different osteopetrotic rat mutations characterized by reduced bone resorption. These three mutations (ia/ia, tl/tl, and op/op) exhibit heterogeneity with respect to osteoclast number and activity and response to being cured by bone marrow transplantation. Calvarial bone osteocalcin was present in normal amounts, but difficult to extract, in ia/ia rats that have increased numbers of inactive osteoclasts. Bone osteocalcin was greatly decreased in op/op (53-60% of control) and tl/tl (64-73% of control) osteopetrotic rats, in which osteoclasts are both reduced in number and inactive. These decreases in osteocalcin levels in bone coexist with elevated serum levels of osteocalcin in all three mutations. Since osteocalcin synthesis is known to be stimulated by 1,25(OH)2D3, the increase in serum osteocalcin may be a reflection of the elevated blood levels of 1,25(OH)2D3 known to occur in each of these mutations. These findings indicate that the composition of osteopetrotic bone is abnormal with respect to osteocalcin in the two rat osteopetrotic mutations showing decreased osteoclast numbers. Considered together with the emerging evidence that the extracellular matrix in many developing tissues plays a role in cell recruitment and differentiation, these data suggest that osteocalcin abnormalities may be a contributing factor to the spectrum of osteoclast aberrations in osteopetrosis.