Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin

Reduced mechanical stress to bone in bedridden patients and astronauts lead s to bone loss acid increase in fracture risk which is one of the major med ical and health issues in modern aging society and space medicine. However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date. Osteopontin (OPN) is one of the major noncollagenous p roteins in bone matrix, but its function in mediating physical-force effect s on bone in vivo has not been known. To investigate the possible requireme nt for OPN in the transduction of mechanical signaling in bone metabolism i n vivo, we examined the effect of unloading on the bones of OPN-/- mice usi ng a tail suspension model. In contrast to the tail suspension-induced bone loss in wild-type mice, OPN-/- mice did not lose bone. Elevation of urinar y deoxypyridinoline levels due to unloading was observed in wild-type but n ot in OPN-/- mice. Analysis of the mechanisms of OPN deficient-dependent re duction in bone on the cellular basis resulted in two unexpected findings. First, osteoclasts, which were increased by unloading in wild-type mice, we re not increased by tail suspension ill OPN-/- mice. Second. measures of os teoblastic bolts formation, which were decreased in wild-type mice by unloa ding, were not altered in OPN-/- mice. These observations indicate that the presence of OPN is a prerequisite for the activation of osteoclastic bone resorption and for the reduction in osteoblastic bone formation in unloaded mice. Thus, OPN is a molecule required for the bone loss induced by mechan ical stress that regulates the functions of osteoblasts and osteoclasts.