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 1

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Expression of RANKL mRNA in bone marrow cells and stromal cells from pat...
Expression of RANKL mRNA in bone marrow cells and stromal cells from patients with Paget’s disease and normal individuals. Total RNA was extracted from normal (Saka) and Paget’s (PSV10) stromal cells or from marrow samples from normal donors and involved bones from patients with Paget’s disease. In addition, bone marrow aspirates were obtained from two normal individuals (N) and from uninvolved (U) and involved (I) bones from two patients with Paget’s disease. RANKL mRNA expression was determined by RT-PCR as described in Methods. RANKL mRNA expression was elevated in six of eight patients with Paget’s disease compared with eight normal donors (a, c), in the PSV10 cell line compared with Saka cells (b), and in the involved bones of both patients (I1 and I2) compared with uninvolved bones (U1 and U2) from these same patients (c). The levels of mRNA expression in uninvolved bones from patients with Paget’s disease were similar to those from normal individuals tested at the same time (N1 and N2). Western blot analysis of marrow samples from a Paget’s patient or a normal donor, and a marrow stromal cell line derived from a Paget’s patient (PSV10 cells) or a normal donor (Saka cells) showed that RANKL expression was increased three- to five-fold in samples from Paget’s disease patients compared with normal cells (d).