Tension in fibrils suppresses their enzymatic degradation - A molecular mechanism for 'use it or lose it'

Abstract

Tissue homeostasis depends on a balance of synthesis and degradation of constituent proteins, with turnover of a given protein potentially regulated by its use. Extracellular matrix (ECM) is predominantly composed of fibrillar collagens that exhibit tension-sensitive degradation, which we review here at different levels of hierarchy. Past experiments and recent proteomics measurements together suggest that mechanical strain stabilizes collagen against enzymatic degradation at the scale of tissues and fibrils whereas isolated collagen molecules exhibit a biphasic behavior that depends on load magnitude. Within a Michaelis-Menten framework, collagenases at constant concentration effectively exhibit a low activity on substrate fibrils when the fibrils are strained by tension. Mechanisms of such mechanosensitive regulation are surveyed together with relevant interactions of collagen fibrils with cells.

Keywords: Collagen; Collagenase; Degradation; Extracellular matrix,; Matrix metalloproteinases (MMPs); Strain; Tissue.

Fig. 1:

Tendon tissue at different length scales, with various factors affecting its enzymatic degradation. (A) Collagen-I fibrils establish the architecture of the tissue. (B) Enzymatic degradation of collagen fibrils depends on conformation of collagen molecules (regulated by intermolecular cross-links between collagen molecules) as well as solution physicochemical factors including temperature, pH, and concentrations of any type of collagenase and collagenase inhibitors present in the tissue.

Fig. 2:

Mechanical response of ECM and cells of tendon-type tissues. (A) Spring-dashpot representation of forces shared by ECM (F_ECM) and Cells (F_Cell) which depend on the type of tissue (tendon, muscle, heart, etc.). ECM components include structural proteins such as collagen (various types) and also adhesion proteins (such as Fibronectin, Vitronectin, Osteonectin) that couple cells to ECM through adhesion receptors. (B) Mechanical strain on tendon tissue is primarily sustained by collagen fibrils present in collagen fibers which results in straightening of their crimps, but strain is also transferred to tenocytes via adhesion receptors.

Fig. 3:

Molecular kinetics and mechanism for strain-suppressed enzymatic degradation of collagen–I molecule within collagen fibrils. (A-i) Michaelis-Menten model states collagenase-collagen dissociation constant (K) increases with tensile strain on collagen fibrils and, (A-ii) collagen fibril degradation rate is suppressed with increasing tensile strain which is evident from (A-iii) respective degradation rates of collagen fibrils (mechanically strained or unstrained) when exposed to MMP-8, obtained using slopes of initial region of collagen conc. vs time curve (adopted from Flynn et al 2010 [77]) (B) Differences between MMP cleavage and BC-driven proteolysis. MMPs have smaller catalytic domains than BC and cut each α-chain of mechanically unloaded collagen molecule sequentially. The only vulnerable cleavage site of a partially unfolded α2-chain (for MMP-1, −8 & −13) is sequestered by mechanical strain. (C) BC cuts all α-chains of unstrained collagen molecule in parallel but the many cleavage sites are sequestered by mechanical strain.