Increased Collagen Turnover Impairs Tendon Microstructure and Stability in Integrin α2β1-Deficient Mice

Integrins are a family of transmembrane proteins, involved in substrate recognition and cell adhesion in cross-talk with the extra cellular matrix. In this study, we investigated the influence of integrin α2β1 on tendons, another collagen type I-rich tissue of the musculoskeletal system. Morphological, as well as functional, parameters were analyzed in vivo and in vitro, comparing wild-type against integrin α2β1 deficiency. Tenocytes lacking integrin α2β1 produced more collagen in vitro, which is similar to the situation in osseous tissue. Fibril morphology and biomechanical strength proved to be altered, as integrin α2β1 deficiency led to significantly smaller fibrils as well as changes in dynamic E-modulus in vivo. This discrepancy can be explained by a higher collagen turnover: integrin α2β1-deficient cells produced more matrix, and tendons contained more residual C-terminal fragments of type I collagen, as well as an increased matrix metalloproteinase-2 activity. A greatly decreased percentage of non-collagenous proteins may be the cause of changes in fibril diameter regulation and increased the proteolytic degradation of collagen in the integrin-deficient tendons. The results reveal a significant impact of integrin α2β1 on collagen modifications in tendons. Its role in tendon pathologies, like chronic degradation, will be the subject of future investigations

Regulation of the Atheroma-Enriched Protein, SPRR3, in Vascular Smooth Muscle Cells through Cyclic Strain is Dependent on Integrin α1β1/Collagen Interaction

Atherosclerotic plaques express high levels of small proline-rich repeat protein (SPRR3), a previously characterized component of the cornified cell envelope of stratified epithelia, where it is believed to play a role in cellular adaptation to biomechanical stress. We investigated the physiological signals and underlying mechanism(s) that regulate atheroma-enriched SPRR3 expression in vascular smooth muscle cells (VSMCs). We showed that SPRR3 is expressed by VSMCs in both human and mouse atheromas. In cultured arterial VSMCs, mechanical cyclic strain, but neither shear stress nor lipid loading induced SPRR3 expression. Furthermore, this upregulation of SPRR3 expression was dependent on VSMC adherence to type I collagen. To link the mechanoregulation of SPRR3 to specific collagen/integrin interactions, we used blocking antibodies against either integrin α1 or α2 subunits and VSMCs from mice that lack specific collagen receptors. Our results showed a dependence on the α1β1 integrin for SPRR3 expression induced by cyclic strain. Furthermore, we showed that integrin α1 but not α2 subunits were expressed on VSMCs within mouse lesions but not in normal arteries. Therefore, we identified the enrichment of the mechanical strain-regulated protein SPRR3 in VSMCs of both human and mouse atherosclerotic lesions whose expression is dependent on the collagen-binding integrin α1β1 on VSMCs. These data suggest that SPRR3 may play a role in VSMC adaptation to local biomechanical stress within the plaque microenvironment

Molecular and cellular basis of scleroderma

Systemic sclerosis (scleroderma) is a chronic inflammatory disease that leads to fibrosis of the skin and involved internal organs. No efficient therapy is currently available. This review summarizes recent progress made in basic as well as clinical science and concludes with a concept that therapy targeting fibrosis in scleroderma needs to take into account the global microenvironment in the skin with its diverse cellular players interacting with a complex extracellular matrix environment and matrix-associated growth factors