Human skin is largely composed of a collagen-rich connective tissue which provides structural and functional support. describes cellular mechanisms that give rise to self-perpetuating collagen fibril fragmentation that creates an age-associated dermal microenvironment (AADM) which contributes to decline of human skin function. [12 26 27 In cultured human skin fibroblasts elevated expression of CCN1 substantially reduces type I procollagen and concurrently increases MMP-1 [12 17 22 In further investigations of CCN1 actions we found that elevated CCN1 in human dermal fibroblasts alters expression of numerous secreted proteins and that the pattern of CCN1-induced alterations closely resemble those observed in aged dermis [12 17 21 27 We refer collectively to CCN1-induced alterations of the dermis as “Age-Associated Dermal Microenvironment (AADM)” (Figure 2). Fig. 2 Model for human skin connective tissue aging CCN1-induced AADM promotes skin connective tissue aging through three major mechanisms: 1) reduced production of dermal ECM components such as type I and type III collagens which contributes to dermal thinning; 2) induction of multiple MMPs (MMP-1 MMP-3 MMP-9 MMP-10 and MMP-23) which promote fragmentation of ECM proteins; and 3) increased expression of pro-inflammatory cytokines NU 6102 (IL-1β IL-6 and IL-8) which promotes inflammatory microenvironment (inflammaging). CCN1-induced AADM accounts for many of the characteristic features of aged human skin dermis including loss of tissue and decline of function. Figure 2 depicts a model in which elevated CCN1 in aged dermal fibroblasts contributes to human skin aging through creating age-associated dermal microenvironment (AADM). Like other organs human skin is exposed to ROS generated from aerobic metabolism. In addition human skin is a major target for a broad spectrum of external stressors such as solar UV radiation as NU 6102 well as microbial and chemical assaults. Chronic exposure to ROS up-regulates CCN1 expression. Elevated CCN1 impairs dermal fibroblast NU 6102 production of collagen by inhibiting TGF-β signaling and promoting production of MMPs and proinflammatory cytokines. These alterations lead to thin and fragmented dermal collagenous ECM characteristic features of aged human skin. Elevated expression of CCN1 in human dermal fibroblasts acts through multiple pathways to promote AADM: 1) impairment of TGF-β signaling by down-regulation of TβRII and thus contributes to age-associated NU 6102 thinning of the dermis [12]; 2) induction of multiple MMPs via up-regulation of transcription factor AP-1 a major regulator of multiple MMPs and thus contributes to age-associated ECM fragmentation [12 21 22 and 3) elevation of multiple pro-inflammatory cytokines and thus contributes to age-associated inflammatory NU 6102 microenvironment (inflammaging) [21 23 CCN1-induced pro-inflammatory cytokines may have a significant impact on the development of AADM. For example IL-1β an AADM-associated cytokines not only up-regulate multiple MMPs but also down-regulates type I collagen synthesis [23]. IL-1β is elevated in the dermis of naturally-aged and photoaged human skin [23]. CCN1 markedly induces IL-1β which in turn contributes to CCN1-mediated reduction of type Rabbit polyclonal to AHCYL1. I collagen expression and induction of MMP-1 expression. Emerging evidence indicates that the CCN family proteins may represent a new class of modulators of inflammation [28]. Consistent with this notion CCN1 activates a proinflammatory genetic program in murine macrophages [29]. Furthermore evidence indicates a potential role of CCN1 in chronic inflammatory diseases such as atherosclerosis rheumatoid arthritis inflammatory kidney diseases and neuroinflammatory diseases [25]. There is strong association of aging with chronic low grade inflammatory activity which may progress to long term tissue damage and systemic chronic inflammation [30]. Accumulating evidence supports the concept of “inflammaging” which posits that low grade chronic elevation of proinflammatory mediators can be a driving force for the aging progress [31]. Central to this concept is that healthy aging is not an inflammatory.