The effect of the degree of sulfation of glycosaminoglycans on osteoclast function and signaling pathways
The effect of the degree of sulfation of glycosaminoglycans on osteoclast function and signaling pathways
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DOI：
10.1016/j.biomaterials.2012.08.028
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发表时间：
2012-11-01
期刊：
影响因子：
14
通讯作者：
Hofbauer, Lorenz C.
中科院分区：
文献类型：
--
作者：
Salbach, Juliane;Kliemt, Stefanie;Hofbauer, Lorenz C.
为了满足老龄化人口日益增长的骨替代需求，开发新型适应性生物材料至关重要。胶原蛋白和糖胺聚糖 (GAG)，例如透明质酸 (HA) 和硫酸软骨素 (CS)，是骨中细胞外基质 (ECM) 的主要成分。我们制造了天然和硫酸盐修饰的 GAG 基质，评估了这些成分如何调节破骨细胞（吸收骨的细胞）的不同功能，并分析了潜在的机制。使用小鼠 RAW264.7 细胞和原代人破骨细胞测试了 GAG 对破骨细胞粘附、活力、分化、形态和吸收以及蛋白质组改变的影响。天然和硫酸化的 GAG 都很稳定，并且基本上无细胞毒性。 GAG 的硫酸化导致破骨细胞分化和吸收的显着抑制，这在很大程度上取决于 GAG 的硫酸化程度而不是单糖组成。硫酸化使再吸收功能显着降低 14% (CS) 和 43% (HA)。高度硫酸化的 GAG 剂量依赖性地抑制破骨细胞分化、破骨细胞特异性 TRAP、组织蛋白酶 K、SWAP-70 和 OSCAR 表达达 63-95%，并抑制参与细胞骨架重排的蛋白质。总之，高度硫酸化的 GAG 显着抑制骨吸收破骨细胞的各种功能。这些特性是否局部有助于改善骨折或骨缺损的愈合需要在体内进行验证。 (C) 2012 Elsevier Ltd. 保留所有权利。
To meet the growing need for bone replacement of our aging population, development of new adaptive biomaterials is essential. Collagen and glycosaminoglycans (GAGs) such as hyaluronan (HA) and chondroitin sulfate (CS) are major components of the extracellular matrix (ECM) in bone. We manufactured native and sulfate-modified GAG matrices, evaluated how these components modulate different functions of osteoclasts, the cells that resorb bone, and analyzed the underlying mechanisms. GAGs were tested for their effects on osteoclast adhesion, viability, differentiation, morphology, and resorption as well as proteome alterations using murine RAW264.7 cells and primary human osteoclasts. Native and sulfated GAGs were stable and largely non-cytotoxic. Sulfation of GAGs led to a significant inhibition of osteoclast differentiation and resorption, which was largely dependent on the degree of sulfation of GAGs rather than the monosaccharide composition. Sulfation significantly reduced resorptive function by 14% (CS) and 43% (HA). Highly sulfated GAGs dose-dependently suppressed osteoclast differentiation, osteoclast-specific expression of TRAP, cathepsin K, SWAP-70, and OSCAR by 63-95%, and inhibited proteins involved in cytoskeletal rearrangement. In conclusion, highly sulfated GAGs significantly inhibit various functions of bone-resorbing osteoclasts. Whether these properties locally contribute to improved fracture or bone defect healing needs to be validated in vivo. (C) 2012 Elsevier Ltd. All rights reserved.