Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-β regulation of osteoclast differentiation
Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-β regulation of osteoclast differentiation
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DOI：
10.1002/jcp.20036
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发表时间：
2004-07-01
影响因子：
5.6
通讯作者：
Oursler, MJ
中科院分区：
文献类型：
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作者：
Karst, M;Gorny, G;Oursler, MJ
为了更好地了解转化生长因子β（TGF-β）在骨代谢中的复杂作用，我们研究了一系列TGF-β浓度对破骨细胞分化的影响。在支持细胞和脾或骨髓破骨细胞前体的共培养物中，低浓度的TGF-β刺激而高浓度抑制分化。我们研究了TGF-β对巨噬细胞集落刺激因子（M-CSF）、NF-κ B配体受体激活因子（RANKL）和骨保护素（OPG）表达的影响，发现M-CSF表达的剂量依赖性抑制。RANKL表达在低TGF-β浓度下升高，OPG的增加幅度较小。在刺激性TGF-β剂量下，OPG的加入阻断了分化。因此，低TGF-β浓度升高了RANKL/OPG比值，而高浓度则没有，这支持了在低TGF-β浓度下，有足够的M-CSF和高RANKL/OPG比值刺激分化。在高TGF-β浓度下，RANKL/OPG比率和M-CSF表达均受到抑制，并且没有分化。我们通过加入M-CSF和/或RANKL检测了TGF-β介导的破骨细胞分化抑制是否是由于这些变化引起的，并且没有观察到任何冲击分化抑制。我们通过用M-CSF和RANKL培养脾或骨髓细胞来研究TGF-β对破骨细胞前体的直接影响。TGF-β处理剂量依赖性地刺激破骨细胞分化。这些数据表明，低TGF-β水平通过影响RANKL/OPG比率刺激破骨细胞分化，而高TGF-β水平通过多种途径抑制破骨细胞分化，包括独立于RANKL/OPG比率或M-CSF表达调控的机制。(C)2004 Wiley-Liss，Inc.
To better understand the complex roles of transforming growth factor-beta (TGF-beta) in bone metabolism, we examined the impact of a range of TGF-beta concentrations on osteoclast differentiation. In co-cultures of support cells and spleen or marrow osteoclast precursors, low TGF-beta concentrations stimulated while high concentrations inhibited differentiation. We investigated the influences of TGF-beta on macrophage colony stimulating factor (M-CSF), receptor activator of NF-kappaB ligand (RANKL), and osteoprotegerin (OPG) expression and found a dose dependent inhibition of M-CSF expression. RANKL expression was elevated at low TGF-beta concentrations with a less dramatic increase in OPG. Addition of OPG blocked differentiation at the stimulatory TGF-beta dose. Thus, low TGF-beta concentrations elevated the RANKL/OPG ratio while high concentrations did not, supporting that, at low TGF-beta concentrations, there is sufficient M-CSF and a high RANKL/OPG ratio to stimulate differentiation. At high TGF-beta concentrations, the RANKL/OPG ratio and M-CSF expression were both repressed and there was no differentiation. We examined whether TGF-beta-mediated repression of osteoclasts differentiation is due to these changes by adding M-CSF and/or RANKL and did not observe any impacton differentiation repression. We studied direct TGF-beta impacts on osteoclast precursors by culturing spleen or marrow cells with M-CSF and RANKL. TGF-beta treatment dose-dependently stimulated osteoclast differentiation. These data indicate that low TGF-beta levels stimulate osteoclast differentiation by impacting the RANKL/OPG ratio while high TGF-beta levels repress osteoclast differentiation by multiple avenues including mechanisms independent of the RANKL/OPG ratio or M-CSF expression regulation. (C) 2004 Wiley-Liss, Inc.