Posttranslational Modifications

Lysyl Oxidase: A Matrix Inhibitor of TGF-β

Science Signaling  09 Dec 2008:
Vol. 1, Issue 49, pp. ec424
DOI: 10.1126/scisignal.149ec424

Transforming growth factor–β1 (TGF-β1) is abundant in the bone matrix and is an important regulator of bone physiology. TGF-β proteins are stored in the extracellular matrix in a latent complex and released upon various stimuli. Atsawasuwan et al. report that lysyl oxidase (LOX), which is an amine oxidase found in bone matrix, interacts with and inhibits TGF-β1 activity. The two proteins coimmunoprecipitated when coexpressed in a bone-derived osteoblast cell line (MC) and interacted in vitro in glutathione S-transferase pull-down experiments. More important, the endogenous proteins were colocalized in the extracellular matrix of cultured MC cells and were isolated as a complex from bone. Transfection of MC cells with a LOX-V5 fusion protein or exogenous addition of LOX-V5 protein inhibited the phosphorylation of Smad3 in response to the addition of recombinant TGF-β1. Inhibiting lysyl oxidase activity of LOX with β-aminopropionitrile (BAPN) restored TGF-β1–induced Smad3 phosphorylation in cells overexpressing LOX or exposed to exogenous LOX-V5, and transfection of a catalytically inactive mutant LOX also had no effect on TGF-β1 signaling. Finally, knockdown of LOX with silencing RNAs in the MC cells enhanced Smad3 phosphorylation in response to recombinant TGF-β1. Questions remain as to whether TGF-β1 is truly a LOX substrate and, if so, whether the crosslinking of TGF-β1 molecules to each other that would likely result would be reversible. However, these results suggest that phenotypes associated with LOX deficiency, which involve bone abnormalities as well as weak tendon and ligament attachments, may not only arise through the effects of LOX on collagen and elastin crosslinking but also involve aberrant TGF-β1 signaling in bone.

P. Atsawasuwan, Y. Mochida, M. Katafuchi, M. Kaku, K. S. K. Fong, K. Csiszar, M. Yamauchi, Lysyl oxidase binds transforming growth factor-β and regulates its signaling via amino oxidase activity. J. Biol. Chem. 283, 34229–34240 (2008). [Abstract] [Full Text]