Table 1.
Summary of major matricellular proteins (MCPs) in systemic sclerosis (SSc) fibrosis
| MCP Family | MCP Family Members Upregulated in SSc | Bound Receptors | General Fibrotic Roles in SSc |
|---|---|---|---|
| CCN [36,42,45,46] | CCN1 | Integrin (α2β1, α6β1, αIIbβ3, αDβ2, αMβ2, αvβ1, αvβ3, αvβ5), syndecan-4 | • Both pro- and antifibrotic roles • CCN1 KO in mice limited type I collagen • Overexpression of CCN1 in SSc dermal fibroblasts downregulates COL1A1 expression |
| CCN2 | Integrins (α4β1, α5β1, α6β1, αMβ2, αvβ1, αvβ3), LRP1, LRP6, syndecan-4, TrkA | • Expression induced by TGFβ-SMAD signaling and mechanotransduction mechanisms • Induces αSMA expression in SSc lung fibroblasts |
|
| CCN3 | Integrins (α5β1, α6β1, αvβ1, αvβ5) | • Overexpression in Tsk1/+ mice downregulates fibrillin-1 and TGFβ/Wnt profibrotic genes | |
| THBS [36,47,48,49,50,51] | THBS-1 | Integrins (αvβ3, αIIbβ3, α9β1, α6β1, α5β1, α4β1, α3β1, α3β1), CD36, CD47, CD148, LRP1, syndecan-3 and -4, calreticulin | • Endogenous activator of latent TGFβ • Enhances contractile activity of SSc fibroblasts by activation of MEK/ERK pathway |
| THBS-2 | Integrins (αvβ3, αIIbβ3, α9β1, α6β1, α4β1), CD36, CD47, LRP1, syndecan-4 | • Silencing in SSc fibroblasts downregulates type I collagen synthesis | |
| THBS-4 | Integrins (β1D, β2, β3) | • Supports collagen deposition (I, II, III, V) and displays proangiogenic effects through TGFβ-SMAD3 signaling | |
| THBS-5 | Integrins (α5β1, αvβ3) | • Promotes aberrant secretion of collagen and fibronectin leading to matrix stiffening | |
| SPARC [52,53,54] | SPARC | Integrin α5β1,TGF-β receptor, endoglin | • Inhibition in SSc dermal fibroblasts downregulates type I collagen and CCN2 • Blocking TGFβ-SMAD2 signaling limits profibrotic functions of SPARC in vitro |
| FSTL1 | Integrin β3 | • Limited reports on fibrotic roles but evidence supports a proangiogenic role in SSc dermal endothelial cells | |
| TN [36,43,44] | TN-C | Integrins (α2β1, α5β1, α7β1, α8β1, α9β1, αvβ3, αvβ6, αvβ1), Syndecan-4, Annexin II, EGFR, TLR4 | • Mediates both profibrotic and inflammatory signaling by TLR4-dependent mechanism • KO mice limits infiltration of myofibroblasts, macrophages, and lymphocytes in pulmonary fibrosis |
| SIBLING [36,55] | OPN | Integrins (αvβ1, αvβ3, αvβ5, αvβ6, α5β1, α8β1, α9β1, α4β7, and α4β1) and CD44 | • Regulates deposition of type I and IV collagen, • Regulates local TGFβ activity • Stimulates myofibroblast proliferation |
| Gla-Family [56] | POSTN | Integrins (αvβ3, αvβ5) | • Colocalizes with αSMA-positive expressing cells in lesional skin • Induces fibroblast differentiation to myofibroblasts • Promotes collagen deposition |
| MGP | Unknown | • No direct studies linking MGP to fibrosis in SSc but may be implicated with calcinosis with SPARC |