BIPHOSPHONATES INDUCE OSTEOBLASTS TO SECRETE AN INHIBITOR OF OSTEOCLAST-MEDIATED RESORPTION

Current knowledge indicates that osteoblasts play an integral role in osteoclastic bone resorption through an osteoclast-stimulating activit y produced by osteoblasts in response to resorption-promoting osteotro pic factors. Previously, we have shown that the inhibitory action of t he bisphosphonates on bone resorption in part is mediated by osteoblas ts. The aim of the present study was to investigate whether the biphos phonate-generated inhibition is due to these compounds decreasing the synthesis of the osteoclast-stimulating activity or is the result of o steoblasts synthesizing an osteoclast resorption inhibitor. Using the osteoblastic cell line CRP 10/30, which produces osteoclast-stimulatin g activity, constitutively and employing isolated rat osteoclasts cult ured on ivory, evidence was obtained indicating that the biphosphonate s ibandronate and alendronate at a concentration of 10(-7) M induce os teoblasts to synthesize an osteoclast inhibitor that reduces pit forma tion by more than 50%. The inhibitor is heat and proteinase labile and has a molecular mass between 1-10 kDa. The reduction of resorption pi ts is paralleled by a decrease in tartrate-resistant acid phosphatase- positive mono- and multinucleated cells, whereas the mean area resorbe d per pit was not changed, suggesting that the inhibitor affects osteo clast formation and/or survival and probably not the osteoclast resorp tion activity. Rat preosteoblastic cells and rat dermal fibroblasts we re found not to produce the inhibitor. In conclusion, osteoblasts asid e from their role of mediating osteoclastic resorption promoters are a lso involved in inhibiting bone resorption through the synthesis of an osteoclast resorption inhibitor.