COLONY-STIMULATING FACTOR-I PLAYS A ROLE IN OSTEOCLAST FORMATION AND FUNCTION IN BONE-RESORPTION INDUCED BY PARATHYROID-HORMONE AND PARATHYROID HORMONE-RELATED PROTEIN

Although colony stimulating factor-1 (CSF-1) plays a key role in osteo clast recruitment, studies examining the effect of CSF-1 on mature ost eoclasts indicate that it may directly inhibit bone resorption by isol ated rat osteoclasts, To define further CSF-1's role in bone remodelin g, we examined the effect of neutralizing antisera to CSF-1 on basal a nd parathyroid hormone (PTH)-induced bone resorption using two organ c ulture assays designed to examine the recruitment of osteoclast precur sors and the activation of mature osteoclasts, respectively. We first assessed whether PTH increases CSF-1 production from bone in organ cul ture by examining conditioned medium fi om 19-day-old fetal rat long b ones in a mitogenesis assay employing a CSF-1-responsive cell line, CR X-1, Conditioned medium from untreated bones induced a titratable incr ease in CRX-1 cell proliferation, and treatment of bones with PTH for 72 h caused a significant increase in mitogenic activity, CSF-1 antise rum caused a significant decrease in mitogenic activity in conditioned medium, indicating that bone in organ culture produces CSF-1 constitu tively and in response to PTR, To examine bone-derived CSF-1's role in bone resorption, we examined the effect of neutralizing antisera to C SF-1 on basal and PTH-induced bone resorption in the fetal rat long bo ne assay, which reflects activation of mature osteoclasts, Anti-CSF-1 caused a significant increase in unstimulated and PTH-induced bone res orption compared with control, By contrast, in the fetal mouse metacar pal assay, which examines proliferation and recruitment of osteoclast progenitors and precursors, anti-CSF-1 caused significant inhibition o f PTH related protein (PTHrP)-induced bone resorption after 3 and 6 da ys of incubation, Consistent with these findings, histological examina tion of cultured 17-day-old fetal metacarpals demonstrated that anti-C SF-1 inhibits the formation of tartrate-resistant acid phosphatase-pos itive osteoclasts in PTHrP-treated explants, whereas it has no effect on unstimulated bones, We conclude that bone-derived CSF-1 may have a dual role in PTH/PTHrP-induced bone resorption by enhancing the appear ance of osteoclast precursors while restraining the resorptive functio n of mature osteoclasts.