Physiological roles of rat fetuin on bone metabolism

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Previously, we reported that a 59 kDa bone sialoprotein purified from rat mandible, is the rat counterpart of human alpha_2-HS glycoprotein and bovine fetuin. Immunohistochemically, this protein is only detectable in calcified tissues such as bone matrices and dentin. In order to study the physiological role of rat fetuin in bone metabolism, the effect of this protein on bone resorption was examined using ^<45>Ca-prelabeled radius of mice. We found that 200 mug/ml of rat fetuin enhanced the activity of bone resorption in the presence of low concentrations (0.1-0.5 nM) of parathyroid hormone (PTH), but it had no activity on bone resorption without PTH.The increase in bone resorption by PTH and PTH plus rat fetuin was inhibited by addition of chymostatin, an inhibitor for cathepsin L.Moreover, we demonstrated that when type I collagen from rat was preincubated with rat fetuin, the digestion of rat type I collagen by cathepsin L was enhanced. These findings suggest that rat fetuin brings about a favorable conformation of type I collagen for the digestion by cathepsin L.During doing above study, we also found that phosphorylated rat fetuin synthesized and secreted by the liver dose-dependently inhibited the mitogenic activity of hepatocyte growth factor (HGF) in vitro. The maximum inhibition was about 50% at the concentration of 1 mug/ml. We showed that this inhibition of HGF activity was due to binding of fetuin to HGF and thus the binding of HGF to its receptor (c-Met) was suppressed. In addition, we have demonstrated that the fetuin concentrations in normal rat serum determined by Western blotting were 2.5-4.5 mg/ml. These concentrations were three orders of magnitude higher than previously published concentrations. Fetuin mRNA level in the liver changes almost in parallel with its serum concentration. Tibia also express fetuin, but much less than the liver.