Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function.
Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function.
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DOI：
10.1210/endo.141.9.7634
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发表时间：
2000-09
期刊：
影响因子：
4.8
通讯作者：
N. Udagawa;N. Takahashi;H. Yasuda;A. Mizuno;K. Itoh;Y. Ueno;T. Shinki;M. Gillespie;T. Martin;K. Higashio;T. Suda
中科院分区：
文献类型：
--
作者：
N. Udagawa;N. Takahashi;H. Yasuda;A. Mizuno;K. Itoh;Y. Ueno;T. Shinki;M. Gillespie;T. Martin;K. Higashio;T. Suda
骨保护素（OPG）是核因子-κ B受体激活剂配体（RANKL）/破骨细胞分化因子的可溶性诱饵受体，可抑制破骨细胞的分化和功能。我们以前报道过，OPG缺乏的小鼠表现出严重的骨质疏松症所造成的骨细胞骨吸收增强。在本研究中，OPG在破骨细胞分化的潜在作用进行了研究，使用小鼠颅骨成骨细胞和骨髓细胞的共培养系统，从OPG缺陷小鼠制备。在不存在骨吸收因子的情况下，在野生型（+/+）或杂合型（+/-）小鼠来源的成骨细胞与纯合型（-/-）小鼠制备的骨髓细胞的共培养物中未形成破骨细胞。与此相反，纯合（-/-）小鼠来源的成骨细胞强烈支持破骨细胞的形成，在与纯合（-/-）骨髓细胞的共培养，即使在骨吸收因子的情况下。OPG与成骨细胞和纯合子（-/-）小鼠骨髓细胞共培养完全抑制自发发生的破骨细胞的形成。向这些共培养物中加入1 α，25-二羟维生素D3 [1 α，25（OH）2D 3]显著增强破骨细胞分化。此外，与野生型（+/+）小鼠相比，来自纯合（-/-）小鼠的胎儿长骨器官培养物中的骨吸收活性显著增加，无论是否存在骨吸收因子。从纯合子（-/-）、杂合子（+/-）和野生型（+/+）小鼠制备的成骨细胞组成性表达相似水平的RANKL信使RNA，1 α，25（OH）2D 3处理后RANKL信使RNA水平同样升高。当纯合（-/-）小鼠来源的成骨细胞和造血细胞共培养，但它们之间的直接接触被阻止，没有破骨细胞形成，即使在1 α，25（OH）2D 3和巨噬细胞集落刺激因子的存在下。这些结果表明，OPG产生的成骨细胞/基质细胞是破骨细胞的分化和功能的生理重要的调节剂，成骨细胞表达的RANKL功能作为膜相关的形式。
Osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoclast differentiation factor, inhibits both differentiation and function of osteoclasts. We previously reported that OPG-deficient mice exhibited severe osteoporosis caused by enhanced osteoclastic bone resorption. In the present study, potential roles of OPG in osteoclast differentiation were examined using a mouse coculture system of calvarial osteoblasts and bone marrow cells prepared from OPG-deficient mice. In the absence of bone-resorbing factors, no osteoclasts were formed in cocultures of wild-type (+/+) or heterozygous (+/-) mouse-derived osteoblasts with bone marrow cells prepared from homozygous (-/-) mice. In contrast, homozygous (-/-) mouse-derived osteoblasts strongly supported osteoclast formation in the cocultures with homozygous (-/-) bone marrow cells, even in the absence of bone-resorbing factors. Addition of OPG to the cocultures with osteoblasts and bone marrow cells derived from homozygous (-/-) mice completely inhibited spontaneously occurring osteoclast formation. Adding 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] to these cocultures significantly enhanced osteoclast differentiation. In addition, bone-resorbing activity in organ cultures of fetal long bones derived from homozygous (-/-) mice was markedly increased, irrespective of the presence and absence of bone-resorbing factors, in comparison with that from wild-type (+/+) mice. Osteoblasts prepared from homozygous (-/-), heterozygous (+/-), and wild-type (+/+) mice constitutively expressed similar levels of RANKL messenger RNA, which were equally increased by the treatment with 1alpha,25(OH)2D3. When homozygous (-/-) mouse-derived osteoblasts and hemopoietic cells were cocultured, but direct contact between them was prevented, no osteoclasts were formed, even in the presence of 1alpha,25(OH)2D3 and macrophage colony-stimulating factor. These findings suggest that OPG produced by osteoblasts/stromal cells is a physiologically important regulator in osteoclast differentiation and function and that RANKL expressed by osteoblasts functions as a membrane-associated form.