IHH as a master coordinator of endochondral bone formation

IHH has actions in endochondral bone formation that do not depend on the stimulation of PTHrP synthesis. This is most clearly demonstrated by the phenotype of Ihh~l~ mice (St-Jacques et al 1999). These mice have very short limbs because of a dramatic decrease in chondrocyte proliferation. Further, in the limbs, these mice are missing osteoblasts both in the bone collar and in the primary spongiosa. Neither of these abnormalities is found in mice missing either PTHrP or the PTH/PTHrP receptor. The absence of osteoblasts in the bone collar and primary spongiosa is consistent with prior tissue culture work that showed that IHH stimulated the osteoblastic differentiation of mesenchymal cells in vitro and that sonic hedgehog induced bone formation when injected subcutaneously in vivo (Kinto et al 1997, Nakamura et al 1997). These data help us to interpret another abnormality found in chimeric bones containing both normal and PTH/ PTHrP receptor~!~ cells. In these bones, bone collar forms much closer to the ends of bones than normal, adjacent to the abnormally located hypertrophic PTH/PTHrP receptor~/~ chondrocytes. In light of the evidence just summarized that Ihh stimulates formation of osteoblasts, perhaps Ihh made by ectopic hypertrophic PTH/PTHrP receptor~!~ chondrocytes stimulates the formation of the abnormally extended bone collar. In support of this idea, the bone collars of the chimeras containing PTH/PTHrP receptor^]

chondrocytes are normal.

These experiments suggest that IHH acts to coordinate the differentiation of both chondrocytes and osteoblasts during endochondral bone formation. IHH, in actions independent of PTHrP, stimulates proliferation of chondrocytes. By stimulating the synthesis of PTHrP, IHH also keeps cells from advancing out of the proliferative pool. At the same time, IHH signals to mesenchyme adjacent to the chondrocytes to stimulate differentiation of cells into osteoblasts. PTHrP action serves to delay the generation of cells that produce IHH. Thus, PTHrP, and probably many other local factors, serve to regulate the regulator, IHH.

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