Department of Oral Biological & Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada; Centre for Blood Research, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada.
Department of Biochemistry & Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada.
Matrix Biol. 2018 Jan;65:30-44. doi: 10.1016/j.matbio.2017.06.004. Epub 2017 Jun 17.
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.
自然衰老过程和各种病理学与结缔组织的组成、结构和机械完整性的改变有关。胶原蛋白是最丰富的基质蛋白，为组织的整体硬度和弹性提供支撑。胶原蛋白的结构变化及其易降解性与皮肤皱纹、骨骼和软骨恶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（MMPs）是组织重塑和胶原蛋白降解的主要贡献者。随着衰老，胶原蛋白会被矿化、晚期糖基化终产物（AGEs）的积累以及糖胺聚糖（GAGs）的耗竭所修饰，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 AGE 修饰的胶原蛋白纤维中的胶原降解减少。GAGs 对 MMP 介导的胶原蛋白降解没有影响。一般来说，MMP 消化会导致天然和改性胶原蛋白纤维的机械强度降低。MMP 和半胱氨酸依赖的胶原酶组织蛋白酶 K（CatK）的连续纤维降解导致它们完全降解。相比之下，非胶原酶组织蛋白酶（如组织蛋白酶 V（CatV））对 MMP 产生的片段的切割作用较弱或几乎没有。总之，我们的数据表明，与衰老和疾病相关的胶原蛋白修饰会降低 MMP 介导的组织重塑，并降低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病理学。
