Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget’s disease of bone
Cheikh Menaa, … , Jan M. Bruder, G. David Roodman
Cheikh Menaa, … , Jan M. Bruder, G. David Roodman
Published June 15, 2000
Citation Information: J Clin Invest. 2000;105(12):1833-1838. https://doi.org/10.1172/JCI9133.
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Article

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

Abstract

Paget’s disease is characterized by highly localized areas of increased osteoclast (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 these possibilities, we compared RANK ligand (RANKL) mRNA expression in a marrow stromal cell line developed from a pagetic lesion (PSV10) with that in a normal stromal cell line (Saka), and expression in marrow samples from affected bones of Paget’s patients with that in normal marrow. RANKL mRNA was increased in PSV10 cells and pagetic marrow compared with Saka cells and normal marrow, and was also increased in marrow from affected bones compared with uninvolved bones from Paget’s patients. Furthermore, pagetic marrow cells formed OCLs at much lower RANKL concentrations than did normal marrow. Anti–IL-6 decreased the RANKL responsivity of pagetic marrow to normal levels, 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 pagetic OCL precursors may contribute to the elevated numbers of OCLs in Paget’s disease.

Authors

Cheikh Menaa, Sakamuri V. Reddy, Noriyoshi Kurihara, Hidefumi Maeda, Dirk Anderson, Tim Cundy, Jillian Cornish, Frederick R. Singer, Jan M. Bruder, G. David Roodman

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Figure 2

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RANKL responsivity of marrow cells from Paget’s patients and normal indi...
RANKL responsivity of marrow cells from Paget’s patients and normal individuals. Marrow cells were processed as described in Methods, and were treated with varying concentrations (0–100 ng/mL) of RANKL, MCSF (25 ng/mL), and 10–7 M dexamethasone. At the end of the culture period, multinucleated cells (MNCs), which cross-reacted with the 23c6 mAb, were scored. In the four experiments shown here, Paget’s samples formed significantly more OCL-like cells at much lower concentrations of RANKL than did normal samples.