Collagen Hybridizing Peptides (CHPs) Elucidate Ursolic Acid's Efficacy in Collagen Homeostasis
Tissue fibrosis, pathologically characterized by the excessive and dysfunctional deposition of extracellular matrix (ECM) components, notably collagen, remains a significant challenge in chronic disease management. Fibrosis accounts for nearly half of all mortality in the United States. Effective therapeutic strategies must engage a dual mechanism, simultaneously arresting neo-collagenesis and actively degrading existing, pathological collagen scar tissue.
A recent study published in Biomolecules utilized Collagen Hybridizing Peptides (CHPs) to provide compelling evidence that ursolic acid (UA), a pentacyclic triterpenoid compound, achieves this necessary dual antifibrotic effect. This effect was demonstrated in primary human dermal fibroblasts and subsequently validated in an in vivo bleomycin-induced mouse model of skin fibrosis.
The historical ambiguity surrounding UA’s influence on collagen—stemming from conflicting reports of both antifibrotic activity and skin-elasticity-improving, collagen-boosting properties—necessitated a high-resolution mechanistic investigation. The researchers definitively established that UA exhibits potent antifibrotic properties through two distinct mechanisms relevant to dermal fibroblasts:
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First, UA significantly suppressed type I collagen expression (Col1A1) at both the mRNA and protein levels. Mechanistically, UA was found to impair the canonical TGF-β/Smad signaling pathway, a principal regulator of collagen synthesis.
Second, and critically, UA markedly stimulated the activity of matrix metalloproteinase-1 (MMP-1), the primary collagen-degrading protease in human skin. This MMP-1 upregulation was mechanistically traced to the activation of the mitogen-activated protein kinase (MAPK) pathways and activator protein 1 (AP-1).
Collagen Hybridizing Peptides (CHPs) were essential for functionally confirming UA's mechanism by providing visual and quantifiable evidence of collagen degradation. By specifically binding to the denatured and unfolded collagen chains created by MMP activity , CHPs demonstrated that the observed upregulation of collagenase mRNA (MMP-3 and MMP-13) translated directly to enhanced dermal collagen degradation in vivo (Figure 6B). This confirmed that UA effectively promotes the necessary breakdown of pathological scar tissue.
Translating these compelling in vitro findings to an in vivo system, the study demonstrated that topical UA application significantly mitigated bleomycin-induced skin thickening and reduced dermal collagen fiber density in mice. Crucially, the researchers employed Collagen Hybridizing Peptides (CHPs) to directly assay and quantify collagen degradation within the mouse skin sections.
CHPs, novel synthetic peptides, specifically bind to the denatured and unfolded collagen chains characteristic of damaged or degraded triple-helix structures. This distinct binding provides a functional probe to evaluate the breakdown phase of collagen homeostasis, a capability traditional structural methods often lack. Fluorescent CHP staining revealed significant collagen degradation in both UA-treated control mice and bleomycin/UA-treated fibrotic mice.
This result conclusively supported the in vitro enzymatic data, confirming that the UA-induced activation of mouse collagenases (MMP-3 and MMP-13, the functional mouse analogs to human MMP-1) facilitated enhanced tissue remodeling by actively breaking down pathological collagen in situ. This mechanism, where UA simultaneously curtails production and promotes degradation, positions it as a highly promising therapeutic agent for addressing the unmet medical need in fibrotic disorders.
Ursolic Acid Inhibits Collagen Production and Promotes Collagen Degradation in Skin Dermal Fibroblasts: Potential Antifibrotic Effects Tianyuan He, Yaping Xiang, Hehui Quan, Yingchun Liu, Chunfang Guo, and Taihao Quan Biomolecules 2025, 15(3): 365 DOI: 10.3390/biom15030365
