Study on Interaction between Osteoclast Progenitors and Osteoblastic Cells in Osteoclast Development.

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We have developed a co-culture system of mouse osteoblastic cells and spleen cells to investigate the interaction of osteoclast progenitors with osteoblastic cells in their differentiation into osteoclasts.Using this co-culture system, we examined [1] role of osteoblastic cells in osteoclast development, [2] pathogenesis of osteopetrotic disorders in op/op (osteopetrotic) and oc/oc (osteosclerotic) mutant mice, and [3] expression of p60^<c-src> (a product of c-src proto-oncogenen) in osteoclasts.[1] Role of Osteoblastic Cells in Osteoclast Development The role of osteoblastic cells in osteoclast development was investigated in a co-culture system of mouse osteoblastic cells and spleen cells. We have shown that osteoblastic cells play an important role in modulating the differentiation of osteoclast progenitors through a mechanism of cell-to-cell interaction (5,6,8). The expression of an osteoclast-inducing factor (s) by osteoblastic cells appeared to be tightly regulated by bone-resorb … More ing factors such as 1alpha,25-dihydroxyvitamin D_3 and parathyroid hormone (1,2,6,11).[2] Pathogenesis of Osteopetrotic Disorders in Mutant Mice We examined pathogenesis of osteopetrotic disorders in op/op and oc/oc mutant mice using a co-culture system of their osteoblastic cells and spleen cells. It was shown that osteoclast deficiency in op/op mice is due to a defect in osteoblastic cells, and that the M-CSF produced by osteoblastic cells plays a critical role in osteoclast development (3). We also found that M-CSF is indispensable for both proliferation of osteoclast progenitors and their differentiation into mature osteoclasts (4, 10). In experiments using oc/oc mice, we concluded that the lack of bone resorption in oc/oc mice is due to a defect of osteoclast progenitors, which fail to differentiate into functional osteoclasts in the microenvironment provided by osteoblastic cells (7).[3] Expression of p60^<c-src> in Osteoclasts Recently, it was reported that the targeted disruption of c-src in mice induced osteopetrosis. We, therefore, examined expression of p60^<c-src> in authentic osteoclasts and osteoclast-like cells formed in the co-culture system. The expression of p60^<c-src> strikingly increased parallel with the appearance of osteoclast-like cells in the co-culture (9). The electron microscopic study revealed that p60^<c-src> was primarily localized on ruffled border membranes and vacuoles (9). These results indicate that p60^<c-src> is important in osteoclastic bone resorption. Less