TY - JOUR
T1 - Aging-associated modifications of collagen affect its degradation by matrix metalloproteinases
AU - Panwar, Preety
AU - Butler, Georgina S.
AU - Jamroz, Andrew
AU - Azizi, Pouya
AU - Overall, Christopher M.
AU - Brömme, Dieter
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - Advanced glycation products
KW - Cathepsins
KW - Collagen
KW - Matrix metalloproteinases
KW - Mineralization
KW - Proteolysis
UR - http://www.scopus.com/inward/record.url?scp=85021214429&partnerID=8YFLogxK
U2 - 10.1016/j.matbio.2017.06.004
DO - 10.1016/j.matbio.2017.06.004
M3 - Article
C2 - 28634008
AN - SCOPUS:85021214429
SN - 0945-053X
VL - 65
SP - 30
EP - 44
JO - Matrix Biology
JF - Matrix Biology
ER -