Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget's disease of bone
Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget's disease of bone
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DOI：
10.1172/jci9133
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发表时间：
2000-06-01
影响因子：
15.9
通讯作者：
Roodman, GD
中科院分区：
文献类型：
--
作者：
Menaa, C;Reddy, SV;Roodman, GD
佩吉特病的特征在于破骨细胞（OCL）活性增加的高度局部区域。这表明pagetic病变的微环境是高度破骨细胞生成的，或者这些病变中的OCL前体对破骨细胞生成因子（或两者）反应过度。为了检验这些可能性，我比较了从Pagetic病变（PSV 10）发展的骨髓基质细胞系与正常基质细胞系（Saka）中RANK配体（RANKL）mRNA的表达，以及佩吉特患者受累骨的骨髓样本与正常骨髓中的表达。与Saka细胞和正常骨髓相比，PSV 10细胞和Pagetic骨髓中的RANKL mRNA增加，并且与佩吉特患者的未受累骨相比，受累骨骨髓中的RANKL mRNA也增加。此外，pagetic骨髓细胞形成OCL的RANKL浓度比正常骨髓低得多。抗IL-6可使正常骨髓的RANKL反应性降低至正常水平，而加入IL-6可增强RANKL反应性。因此，RANKL的表达和反应性在部分由IL-6介导的pagetic病变中增加。这些数据表明，受累骨中RANKL表达增强和Pagetic OCL前体的RANKL敏感性增加可能导致佩吉特病中OCL数量增加。
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, me 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.