Cryptic fragment alpha4 LG4-5 derived from laminin alpha4 chain inhibits de novo adipogenesis by modulating the effect of fibroblast growth factor-2

• Published in: Development, growth & differentiation growth & differentiation, 2008-02, Vol.50 (2), p.97-107
• Main Authors: Yamashita, Hironobu, Goto, Chie, Tajima, Rie, Koparal, Ayse Tansu, Kobori, Masato, Ohki, Yuji, Shitara, Kenya, Narita, Ryo, Toriyama, Kazuhiro, Torii, Shuhei, Niimi, Tomoaki, Kitagawa, Yasuo
• Format: Article
• Language: English
• Subjects: Adipogenesis; Animals; Cells, Cultured; CHO Cells; Chromatography, Affinity; Collagen - metabolism; Cricetinae; Cricetulus; Drug Combinations; Fibroblast Growth Factor 2 - metabolism; Heparin - metabolism; In Vitro Techniques; Laminin - chemistry; Laminin - genetics; Laminin - metabolism; Mice; Mice, Nude; Models, Biological; Pancreatic Elastase - metabolism; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Protein Structure, Tertiary; Proteoglycans - metabolism; Recombinant Proteins - metabolism; Swine; Syndecan-2 - chemistry; Syndecan-2 - metabolism; Syndecan-4 - chemistry; Syndecan-4 - metabolism
• ISSN: 1440-169X

Cleavage of the extracellular matrix (ECM) by proteolysis unmasks cryptic sites and generates novel fragments with biological activities functionally distinct from those of the intact ECM molecule. The laminin G-like (LG)4-5 fragment has been shown to be excised from the laminin alpha4 chain in various tissues. However, the functional role of this fragment has remained unknown to date. To investigate this, we prepared alpha4 LG1-3 and alpha4 LG4-5 fragments by elastase digestion of recombinant alpha4 LG1-5, and examined their effects on de novo adipogenesis in mice at the site of injection of basement membrane extract (Matrigel) and fibroblast growth factor (FGF)-2. Although the addition of whole alpha4 LG1-5 suppressed adipogenesis to some extent, the alpha4 LG4-5 fragment could strongly suppress adipogenesis at a concentration of less than 20 nm. Addition of the alpha4 LG4 module, which contains a heparin-binding region, had a suppressive effect, but this was lost in mutants with reduced heparin-binding activity. In addition, antibodies against the extracellular domain of syndecan-2 and -4, which are known receptors for the alpha4 LG4 module, suppressed adipogenesis. Thus, these results suggest that the cryptic alpha4 LG4-5 fragment derived from the laminin alpha4 chain inhibits de novo adipogenesis by modulating the effect of FGF-2 through syndecans.