Characterization of the Response of Primary Cells Relevant to Dialysis-Related Amyloidosis to β2-Microglobulin Monomer and Fibrils
Characterization of the Response of Primary Cells Relevant to Dialysis-Related Amyloidosis to β2-Microglobulin Monomer and Fibrils
复制标题
与透析相关淀粉样变性相关的原代细胞对 β2-微球蛋白单体和原纤维反应的表征
作者：
M. Porter;Katy E. Routledge;S. Radford;E. Hewitt
不溶性淀粉样蛋白原纤维的形成与一系列毁灭性的人类疾病有关。透析相关性淀粉样变性（dialysis related amyloidosis，简称AAD）是血液透析的一种严重并发症，可导致骨和关节的进行性破坏。血液透析受试者血清中β2-微球蛋白（β 2 m）浓度升高可促进骨关节组织中淀粉样纤维的形成，但对骨关节炎中这些组织破坏的细胞基础知之甚少。在本研究中，我们对单体和纤维状β 2 m与滑膜关节中存在的原代人细胞类型的相互作用进行了系统分析。基于巨噬细胞浸润体内β 2 m淀粉样蛋白沉积的观察结果，我们证明单核细胞（巨噬细胞的前体）不能降解β 2 m原纤维，并且单体β 2 m和纤维状β 2 m对这些细胞都具有细胞毒性。β 2 m原纤维还损害单核细胞形成骨吸收破骨细胞，并降低成骨细胞（生成骨的细胞类型）的活力。因此，我们预测β 2 m淀粉样蛋白将破坏骨的重塑，这对于维持该组织至关重要。此外，我们发现β 2 m原纤维降低了软骨细胞的活力，从而合理化了骨关节炎中软骨的损失。总之，我们的观察结果表明，β 2 m细胞毒性在骨关节组织中具有多个细胞靶点，并且可能是骨关节炎骨和关节破坏特征的关键因素。
The formation of insoluble amyloid fibrils is associated with an array of devastating human diseases. Dialysis-related amyloidosis (DRA) is a severe complication of hemodialysis that results in the progressive destruction of the bones and joints. Elevated concentrations of β2-microglobulin (β2m) in the serum of subjects on hemodialysis promote the formation of amyloid fibrils in the osteoarticular tissues, but the cellular basis for the destruction of these tissues in DRA is poorly understood. In this study we performed a systematic analysis of the interaction of monomeric and fibrillar β2m with primary human cells of the types present in the synovial joints of subjects with DRA. Building upon observations that macrophages infiltrate β2m amyloid deposits in vivo we demonstrate that monocytes, the precursors of macrophages, cannot degrade β2m fibrils, and that both monomeric β2m and fibrillar β2m are cytotoxic to these cells. β2m fibrils also impair the formation of bone resorbing osteoclasts from monocytes and reduce the viability of osteoblasts, the cell type that produces bone. As a consequence, we predict that β2m amyloid will disrupt the remodelling of the bone, which is critical for the maintenance of this tissue. Moreover, we show that β2m fibrils reduce the viability of chondrocytes, rationalizing the loss of cartilage in DRA. Together, our observations demonstrate that β2m cytotoxicity has multiple cellular targets in the osteoarticular tissues and is likely to be a key factor in the bone and joint destruction characteristic of DRA.
DOI：
10.1016/0006-291x(85)91948-5
发表时间：
1985-01-01
影响因子：
3.1
作者：
GEJYO, F;YAMADA, T;SCHMID, K
通讯作者：
SCHMID, K