Distinct structural forms of type I collagen modulate cell cycle regulatory proteins in mesangial cells

Background. Extracellular matrix molecules profoundly regulate cell behavior, including proliferation. In glomerulonephritis, type I collagen accumulates in the mesangium and is constantly structurally modified and degraded during the course of the disease. Methods. We studied how two structurally distinct forms of type I collagen, monomer versus polymerized fibrils. affect cell proliferation, mitogen-activated protein kinase (MAPK) activation, and expression of GI-phase regulatory proteins in cultured rat mesangial cells (MCs). To analyze the possible involvement of collagen-binding integrins in type T collagen-derived growth signals further, distribution patterns of integrin chains were examined by immunocytochemistry. Results. Polymerized type I collagen completely prevented the increase of DNA synthesis and cell replication induced by 5% fetal calf serum (FCS) or 25 ng/mL platelet-derived growth factor (PDGF) in MCs on monomer type I collagen. Protein expression of cyclins DI and E was markedly down-regulated in MCs plated on polymerized type I collagen for eight hours in 5% FCS. as compared with MCs on monomer type I collagen. Incubation with 5% FCS reduced expression of the cdk-inhibitor protein p27(Kip1) On monomer but not on polymerized type I collagen. Moreover. polymerized type I collagen markedly reduced cyclin E-associated kinase activity in the presence of 5% FCS. Polymerized type I collagen diminished the PDGF-induced phosphorylation and nuclear translocation of p42/p44 MAPK, but did not affect phosphorylation of PDGF beta-receptors. In MCs plated on monomer type I collagen, alpha(1), alpha(2), and beta(1) integrin chains were recruited into focal contacts. However, on polymerized type I collagen, alpha(2) and beta(1), but not alpha(1), integrin chains were condensed into focal contacts. Conclusions. The growth-inhibitory effect of polymerized type I collagen is characterized by rapid changes of expression and/or activation of MAPK and G(1)-phase regulators and could result from the lack of alpha(1)beta(1) integrin signaling in MCs on polymerized type I collagen. Conceivably, deposition of polymerized type I collagen might reflect a reparative response to control MC replication in glomerular inflammation.