Abstract
The role of the microenvironment in driving connective tissue disease is being increasingly appreciated. Matricellular proteins of the CCN family are signaling modifiers that are secreted by cells into the extracellular matrix microenvironment where they have profound, context-dependent effects on organ development, homeostasis and disease. Indeed, CCN proteins are emergent targets for therapeutic intervention. Recent evidence suggests that, in vivo, CCN3 has effects opposing CCN2. Moreover, when CCN3 expression is high, CCN2 expression is low. That is, they appear to be regulated in a yin/yang fashion, leading to the hypothesis that the CCN2:CCN3 ratio is important to control tissue homeostasis. To begin to test the hypothesis that alterations in CCN2:CCN3 expression might be important in skin biology in vivo, we evaluated the relative ex vivo effects of the profibrotic protein TGFbeta1 on dermal fibroblasts on protein and RNA expression of CCN3 and CCN2, as well as the related protein CCN1. We also used signal transduction inhibitors to begin to identify the signal transduction pathways controlling the ability of fibroblasts to respond to TGFbeta1. As anticipated, CCN1 and CCN2 protein and mRNA were induced by TGFbeta1 in human dermal fibroblasts. This induction was blocked by TAK1, FAK, YAP1 and MEK inhibition. Conversely, TGFbeta1 suppressed CCN3 mRNA expression in a fashion insensitive to FAK, MEK, TAK1 or YAP1 inhibition. Unexpectedly, CCN3 protein was not detected in human dermal fibroblasts basally. These data suggest that, in dermal fibroblasts, the profibrotic protein TGFbeta1 has a divergent effect on CCN3 relative to CCN2 and CCN1, both at the mRNA and protein level. Given that the major source in skin in vivo of CCN proteins are fibroblasts, our data are consistent that alterations in CCN2/CCN1: CCN3 ratios in response to profibrotic agents such as TGFbeta1 may play a role in connective tissue pathologies including fibrosis.
Highlights
Fibrosis, as a pathology, is characterized by excessive deposition of extracellular matrix, comprised principally of type I collagen, resulting in scar tissue that culminates in organ dysfunction and death
TGFbeta1 induced CCN2 mRNA protein in a fashion sensitive to ALK5 inhibition; TGFbeta1 suppressed CCN3 mRNA expression; this was blocked by addition of ALK5 inhibitor (Fig 1)
CCN proteins share a similar structure, and have limited in vitro effects, making the development of relevant cell-based bioassays extremely difficult; is is necessary to study the functional role of CCN proteins in vivo. [15, 30] Of these, CCN2 (CTGF) is the most studied; anti-CCN2 antibodies are in clinical development [23]
Summary
As a pathology, is characterized by excessive deposition of extracellular matrix, comprised principally of type I collagen, resulting in scar tissue that culminates in organ dysfunction and death. The effector cell of fibrosis is the fibroblast, which responds to profibrotic cytokines such as TGFbeta by increasing production, contraction, adhesion and remodeling of the surrounding extracellular matrix [2, 4]. It was believed, owing to its profound in vitro and in vivo effects and its potent upregulation in connective tissue disease, that targeting TGFbeta and its canonical signaling pathways would have profound palliative effects on fibrotic conditions. Parallel studies examining: (1) non-canonical TGFbeta signaling; (2) the mechanobiology of the profibrotic effector cell, the myofibroblast; and (3) collagen structure conclusively established that an enhanced, autocrine pro-adhesive signaling pathway was essential to promote and sustain fibrosis [7,8,9,10,11]
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