CCN proteins as potential actionable targets in scleroderma

Abstract

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease combining inflammatory, vasculopathic and fibrotic manifestations. Skin features, which give their name to the disease and are considered as diagnostic as well as prognostic markers, have not been thoroughly investigated in terms of therapeutic targets. CCN proteins (CYR61/CCN1, CTGF/CCN2, NOV/CCN3 and WISP1‐2‐3 as CCN4‐5‐6) are a family of secreted matricellular proteins implicated in major cellular processes such as cell growth, migration, differentiation. They have already been implicated in key pathophysiological processes of SSc, namely fibrosis, vasculopathy and inflammation. In this review, we discuss the possible implication of CCN proteins in SSc pathogenesis, with a special focus on skin features, and identify the potential actionable CCN targets.

Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/ acne inversa

“…Such insights may help explain why certain patients are prone to hypertrophic scarring, tunnelling and tract formation, and the mechanisms underlying these presentations. This may also lead to the identification of novel therapeutic targets which overlap with pipeline drugs for fibrotic diseases . A large body of literature exists regarding epidermal‐stromal interactions in the setting of cutaneous melanoma and other inflammatory disorders such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD); however, investigations in inflammatory skin disease are limited.…”

The Roles of CCN1/CYR61 in Pulmonary Diseases

“…Accumulated data suggested CCN1 is a multifunctional protein, which is essential for physiological processes such as embryonic development, tissue injury repair, senescence, and angiogenesis [ 24 , 25 ]. Later, CCN1 was also found to participate in pathological processes, including but not limited to arthritis, fibrosis, atherosclerosis, and cancer [ 26 , 27 , 28 , 29 , 30 ]. CCN1 is a rapid response gene to a wide range of stimulation.…”

Emerging Roles of Matricellular Proteins in Systemic Sclerosis

“…Of greatest structural significance to this family of proteins is their unique tetramodular organization that confer vast biological properties acting both independently and/or complementary to one another [ 57 ]. Loss of tight spatial-temporal regulation of CCN proteins in wound healing triggers a maladaptive repair program affecting processes of inflammation, proliferation, and tissue remodeling that can lead to development of fibrosis-related pathologies such as SSc [ 58 , 59 , 60 ]. Amongst the CCN family, CCN1 and CCN2 make up the majority of MCPs studied in SSc research while CCN3-6 are less understood but have emerging functions.…”