Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget's disease of bone

Paget's disease is characterized by highly localized areas of increased ost eoclast (OCL) activity. This suggests that the microenvironment in pagetic lesions is highly osteoclastogenic, or that OCL precursors in these lesions are hyperresponsive to osteoclastogenic factors (or both). To examine thes e possibilities, me compared RANK ligand (RANKL) mRNA expression in a marro w stromal cell line developed from a pagetic lesion (PSV10) with that in a normal stromal cell line (Saka), and expression in marrow samples from affe cted bones of Paget's patients with that in normal marrow. RANKL mRNA was i ncreased in PSV10 cells and pagetic marrow compared with Saka cells and nor mal marrow, and was also increased in marrow from affected bones compared w ith uninvolved bones from Paget's patients. Furthermore, pagetic marrow cel ls formed OCLs at much lower RANKL, concentrations than did normal marrow. Anti-IL-6 decreased the RANKL responsivity of pagetic marrow to normal leve ls, whereas addition of IL-6 to normal marrow enhanced RANKL responsivity. Thus, RANKL expression and responsivity is increased in pagetic lesions, in part mediated by IL-6. These data suggest that the combination of enhanced expression of RANKL in affected bones and increased RANKL sensitivity of p agetic OCL precursors may contribute to the elevated numbers of OCLs in Pag et's disease.