Age-related collagen turnover of the interstitial matrix and basement membrane: Implications of age- and sex-dependent remodeling of the extracellular matrix

Abstract

The extracellular matrix (ECM) plays a vital role in maintaining normal tissue function. Collagens are major components of the ECM and there is a tight equilibrium between degradation and formation of these proteins ensuring tissue health and homeostasis. As a consequence of tissue turnover, small collagen fragments are released into the circulation, which act as important biomarkers in the study of certain tissue-related remodeling factors in health and disease. The aim of this study was to establish an age-related collagen turnover profile of the main collagens of the interstitial matrix (type I and III collagen) and basement membrane (type IV collagen) in healthy men and women. By using well-characterized competitive ELISA-assays, we assessed specific fragments of degraded (C1M, C3M, C4M) and formed (PINP, Pro-C3, P4NP7S) type I, III and IV collagen in serum from 617 healthy men and women ranging in ages from 22 to 86. Subjects were divided into 5-year age groups according to their sex and age. Groups were compared using Kruskal-Wallis adjusted for Dunn's multiple comparisons test and Mann-Whitney t-test. Age-specific changes in collagen turnover was most profound for type I collagen. PINP levels decreased in men with advancing age, whereas in women, the level decreased in early adulthood followed by an increase around the age of menopause (age 40-60). Sex-specific changes in type I, III and IV collagen turnover was present at the age around menopause (age 40-60) with women having an increased turnover. In summary, collagen turnover is affected by age and sex with the interstitial matrix and the basement membrane being differently regulated. The observed changes needs to be accounted for when measuring ECM related biomarkers in clinical studies.

Fig 1. Type I collagen turnover as function of age.

Biomarkers reflecting degradation and formation of type I collagen were measured in serum from 303 healthy men and 314 healthy women aged 22–86 divided into 5-year age groups. (A) Formation of interstitial type I collagen (PINP) and (B) degradation of interstitial type I collagen (C1M). Statistical significance of C1M and PINP between each age group was calculated using ANOVA comparing the mean of each group with the mean of every other group and is presented at the different age groups in S1 Table. All data are shown as median and interquartile range.

Fig 2. Type III collagen turnover as function of age.

Biomarkers reflecting degradation and formation of type III collagen were measured in serum from 303 healthy men and 314 healthy women aged 22–86 divided into 5-year age groups. (A) Formation of interstitial type III collagen (Pro-C3) and (B) degradation of interstitial type III collagen (C3M). Statistical significance of C3M and Pro-C3 between each age group was calculated using ANOVA comparing the mean of each group with the mean of every other group and is presented at the different age groups in S1 Table. All data are shown as median and interquartile range.

Fig 3. Type IV collagen turnover as function of age.

Biomarkers reflecting degradation and formation of type IV collagen were measured in serum from 303 healthy men and 314 healthy women aged 22–86 divided into 5-year age groups. (A) Formation of basement membrane type IV collagen (P4NP7S) and (B) degradation of basement membrane type IV collagen (C4M). Statistical significance of C4M and P4NP7S between each age group was calculated using ANOVA comparing the mean of each group with the mean of every other group and is presented at the different age groups in S1 Table. All data are shown as median and interquartile range.