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Aging-associated modifications of collagen affect its degradation by matrix metalloproteinases.
Matrix Biology ( IF 6.9 ) Pub Date : 2017-06-22 , DOI: 10.1016/j.matbio.2017.06.004
Preety Panwar 1 , Georgina S Butler 1 , Andrew Jamroz 1 , Pouya Azizi 2 , Christopher M Overall 3 , Dieter Brömme 3
Affiliation  

The natural aging process and various pathologies correlate with alterations in the composition and the structural and mechanical integrity of the connective tissue. Collagens represent the most abundant matrix proteins and provide for the overall stiffness and resilience of tissues. The structural changes of collagens and their susceptibility to degradation are associated with skin wrinkling, bone and cartilage deterioration, as well as cardiovascular and respiratory malfunctions. Here, matrix metalloproteinases (MMPs) are major contributors to tissue remodeling and collagen degradation. During aging, collagens are modified by mineralization, accumulation of advanced glycation end-products (AGEs), and the depletion of glycosaminoglycans (GAGs), which affect fiber stability and their susceptibility to MMP-mediated degradation. We found a reduced collagenolysis in mineralized and AGE-modified collagen fibers when compared to native fibrillar collagen. GAGs had no effect on MMP-mediated degradation of collagen. In general, MMP digestion led to a reduction in the mechanical strength of native and modified collagen fibers. Successive fiber degradation with MMPs and the cysteine-dependent collagenase, cathepsin K (CatK), resulted in their complete degradation. In contrast, MMP-generated fragments were not or only poorly cleaved by non-collagenolytic cathepsins such as cathepsin V (CatV). In conclusion, our data indicate that aging and disease-associated collagen modifications reduce tissue remodeling by MMPs and decrease the structural and mechanic integrity of collagen fibers, which both may exacerbate extracellular matrix pathology.

中文翻译:

胶原蛋白的老化相关修饰会影响其被基质金属蛋白酶降解。

自然衰老过程和各种病理状况与结缔组织的组成以及结构和机械完整性的变化有关。胶原蛋白代表最丰富的基质蛋白,可提供组织的整体刚度和弹性。胶原蛋白的结构变化及其对降解的敏感性与皮肤起皱,骨骼和软骨退化以及心血管和呼吸系统功能障碍有关。在这里,基质金属蛋白酶(MMP)是组织重塑和胶原蛋白降解的主要因素。在老化过程中,胶原蛋白会因矿化,高级糖基化终产物(AGEs)的积累和糖胺聚糖(GAGs)的消耗而被修饰,这会影响纤维的稳定性及其对MMP介导的降解的敏感性。与天然原纤维胶原蛋白相比,我们发现矿化和经AGE修饰的胶原蛋白纤维的胶原蛋白溶解减少。GAG对MMP介导的胶原蛋白降解没有影响。通常,MMP消化会导致天然和改性胶原纤维的机械强度降低。带有MMP和半胱氨酸依赖性胶原酶组织蛋白酶K(CatK)的连续纤维降解导致其完全降解。相比之下,MMP生成的片段不会或仅差地被非胶原分解组织蛋白酶(例如组织蛋白酶V(CatV))切割。总之,我们的数据表明,衰老和与疾病相关的胶原蛋白修饰减少了MMPs对组织的重塑,并降低了胶原蛋白纤维的结构和机械完整性,这两者都可能加剧细胞外基质的病理。
更新日期:2019-11-01
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