Indian hedgehog is an essential component of mechanotransduction complex to stimulate chondrocyte proliferation

Indian hedgehog (Ihh), a member of the vertebrate hedgehog morphogen family , is a key signaling molecule that controls chondrocyte proliferation and d ifferentiation. In this study, we show a novel function of Ihh. Namely, it acts as an essential mediator of mechanotransduction in cartilage. Cyclic m echanical stress greatly induces the expression of Ihh by chondrocytes. Thi s induction is abolished by gadolinium, an inhibitor of stretch-activated c hannels. This suggests that the IHH gene is mechanoresponsive. The mechano- induction of Ihh is essential for stimulating chondrocyte proliferation by mechanical loading. The presence of an Ihh functional blocking antibody dur ing loading completely abolishes the stimulatory effect of mechanical load on proliferation. Furthermore, Ihh mediates the mechanotransduction process in a bone morphogenic protein (BMP)-dependent and parathyroid hormone-rela ted peptide-independent manner. BMP 2/4 are up-regulated by mechanical stre ss through the induction of Ihh, and BMP antagonist noggin inhibits mechani cal stimulation of chondrocyte proliferation. This suggests BMP lies downst ream of Ihh in mechanotransduction pathway. Our data suggest that Ihh may t ransduce mechanical signals during cartilage growth and repair processes.