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Roles of stromal cell RANKL, OPG, and M‐CSF expression in biphasic TGF‐β regulation of osteoclast differentiation
Author(s) -
Karst Mary,
Gorny Genevieve,
Galvin Rachelle J. Sells,
Oursler Merry Jo
Publication year - 2004
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20036
Subject(s) - rankl , osteoclast , osteoprotegerin , endocrinology , medicine , chemistry , cellular differentiation , transforming growth factor beta , macrophage colony stimulating factor , stromal cell , rank ligand , transforming growth factor , activator (genetics) , receptor , microbiology and biotechnology , biology , macrophage , in vitro , biochemistry , gene
To better understand the complex roles of transforming growth factor‐beta (TGF‐β) in bone metabolism, we examined the impact of a range of TGF‐β concentrations on osteoclast differentiation. In co‐cultures of support cells and spleen or marrow osteoclast precursors, low TGF‐β concentrations stimulated while high concentrations inhibited differentiation. We investigated the influences of TGF‐β on macrophage colony stimulating factor (M‐CSF), receptor activator of NF‐κB ligand (RANKL), and osteoprotegerin (OPG) expression and found a dose dependent inhibition of M‐CSF expression. RANKL expression was elevated at low TGF‐β concentrations with a less dramatic increase in OPG. Addition of OPG blocked differentiation at the stimulatory TGF‐β dose. Thus, low TGF‐β concentrations elevated the RANKL/OPG ratio while high concentrations did not, supporting that, at low TGF‐β concentrations, there is sufficient M‐CSF and a high RANKL/OPG ratio to stimulate differentiation. At high TGF‐β concentrations, the RANKL/OPG ratio and M‐CSF expression were both repressed and there was no differentiation. We examined whether TGF‐β‐mediated repression of osteoclasts differentiation is due to these changes by adding M‐CSF and/or RANKL and did not observe any impact on differentiation repression. We studied direct TGF‐β impacts on osteoclast precursors by culturing spleen or marrow cells with M‐CSF and RANKL. TGF‐β treatment dose‐dependently stimulated osteoclast differentiation. These data indicate that low TGF‐β levels stimulate osteoclast differentiation by impacting the RANKL/OPG ratio while high TGF‐β levels repress osteoclast differentiation by multiple avenues including mechanisms independent of the RANKL/OPG ratio or M‐CSF expression regulation. © 2004 Wiley‐Liss, Inc.