Age-dependent regulation of cell-mediated collagen turnover

JCI Insight. 2020 May 21;5(10):e137519. doi: 10.1172/jci.insight.137519.

Abstract

Although aging represents the most important epidemiologic risk factor for fibrotic disease, the reasons for this are incompletely understood. Excess collagen deposition in tissues is the sine qua non of tissue fibrosis and can be viewed as an imbalance between collagen production and collagen degradation. Yet we still lack a detailed understanding of the changes that take place during development, maturation, and aging in extracellular matrix (ECM) dynamics. Resolution of fibrosis is impaired in aging, and this impairment may explain why age is the most important risk factor for fibrotic diseases, such as idiopathic pulmonary fibrosis. However, ECM dynamics and impaired resolution of fibrosis in aging remain understudied. Here we show that cell-mediated collagen uptake and degradation are diminished in aged animals and this finding correlates with downregulation of the collagen endocytic receptor mannose receptor, C-type 2 (Mrc2). We identify myeloid zinc finger-1 as a potentially novel transcriptional regulator of Mrc2, and both this transcription factor and Mrc2 are downregulated in multiple tissues and organisms in an age-dependent manner. Thus, cell-mediated degradation of collagen is an essential process that promotes resolution of fibrosis, and impairment in this process contributes to age-related fibrosis.

Keywords: Aging; Collagens; Extracellular matrix; Fibrosis; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Collagen / genetics
  • Collagen / metabolism*
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism*
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Proteolysis*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Transcription, Genetic

Substances

  • Kruppel-Like Transcription Factors
  • Membrane Glycoproteins
  • Mrc2 protein, mouse
  • Mzf1 protein, mouse
  • Receptors, Cell Surface
  • Collagen