Reduction of fibroblast size/mechanical force down‐regulates TGF‐β type II receptor: implications for human skin aging

Summary

The structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix ( ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (Tβ RII) and thus impairs TGF‐β/Smad signaling pathway. Both Tβ RII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of Tβ RII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor ( CTGF/ CCN2). Restoration of Tβ RII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of Tβ RII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of Tβ RII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.