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Assembly and remodeling of collagen and elastic fibers in pathophysiology: Proteases have the final cut
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DOI：10.1111/febs.70608.png)
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Abstract
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The extracellular matrix (ECM) provides both architectural integrity and signaling cues to tissues, largely through its fibrous components—collagen and elastin. Collagen fibrils consist of a core of various collagen types associated with several non-collagenous binding partners and confer tensile strength to tissues, while elastic fibers, composed of cross-linked elastin on a fibrillin-rich scaffold, ensure elasticity and resilience. Far from being mere degradative enzymes, proteases are key regulators of both the assembly and turnover of these networks. Metalloproteinases of the BMP1/tolloid-like, meprin and ADAMTS families orchestrate procollagen maturation, while lysyl oxidases and related enzymes drive covalent cross-linking of collagen and elastin fibers, also under proteolytic control. Matrix metalloproteinases (MMPs) and cysteine cathepsins further modulate collagen structure and degradation, generating bioactive fragments used as clinical biomarkers. In parallel, ADAMTS and ADAMTS-like proteases orchestrate fibrillin microfibril organization, fibulin interactions, and the topography of elastogenesis. Elastolytic proteases—including cathepsins K, S, and V, as well as MMP2, MMP7, MMP9, and MMP12—mediate physiological remodeling but also fuel pathological states when dysregulated, releasing elastin-derived peptides that act as potent signaling matrikines. Genetic or acquired defects in these proteolytic pathways underlie diverse connective tissue diseases such as osteogenesis imperfecta, Ehlers–Danlos, and acromelic dysplasias, as well as fibrosis, emphysema, and vascular aging. This review integrates recent structural, biochemical, and pathological insights into how proteases coordinate collagen and elastin dynamics, highlighting novel therapeutic strategies—including substrate- and exosite-selective inhibitors—to restore ECM homeostasis while minimizing off-target effects.
Keywords:
collagen
connective tissue disorders
elastin
extracellular matrix
fiber remodeling
proteases
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