Pulling on a cytokine

In This Issue In This Issue Pulling on a cytokine he extracellular matrix (ECM) acts as a storage facility for tons of factors waiting to do business in the cell. Annes et al. (page 723) show that the ECM anchoring of one factor, the cytokine TGF-␤ , is essential for its activation. The anchoring may give cells something to pull against, with the pulling mediating the activation. Most TGF-␤ is secreted as a complex containing TGF-␤ , a TGF-␤ pro-domain, and a protein called the latent TGF-␤ binding protein (LTBP). By the time the complex is extracellular, the T An artificial tether (anti-HA; triangles) activates just as well as LTBP. pro-domain has been cleaved from TGF-␤ but remains non-covalently bound to TGF-␤ and covalently linked (via disulfides) to LTBP. The pro-domain stops TGF-␤ from signaling, but the complex can be activated in the presence of cells expressing the integrin ␣ V ␤ 6. The mechanism of TGF-␤ activation remained a mystery. The authors first established that TGF-␤ plus its TGF-␤ pro-domain could not be activated by ␣ V ␤ 6 in the absence of LTBP. Further-Mineralized mice ot's wife turned into a pillar of salt because she looked back at Sodom and Gomorrah; but most people are saved from being turned into one big pile of minerals by min-eralization inhibitors. Murshed et al. (page 625) now show that these inhibitors act locally and selectively despite circulating systemically. A better understanding of how this works could suggest ways to tackle the ectopic mineralization seen during arthritis. Mineralization is necessary in bone, but must be prevented in soft tissues—such as artery walls and cartilage—that have an extensive, mineralization-prone extracellular matrix (ECM). It is unclear how this distinction is made by inhibitors that are made locally but also circulate systemically. Murshed et al. investigated this process by expressing a known mineralization inhibitor, Matrix gla L Mineralization (red) of the aorta is prevented by local (left), but not global (right), Mgp expression. protein (MGP), in various mouse tissues. MGP could act locally when expressed locally: expression in arterial walls inhibited the ectopic mineraliza-tion normally seen there in mice lacking MGP; and expression in bone-generating osteoblasts reduced bone mineralization in wild-type mice. But MGP expressed in liver, so that it reached high levels in the bloodstream , did not have such effects. Although the resulting serum could inhibit osteoblast miner-alization in vitro, there was no …