IHH and endochondral bone formation

When IHH was overexpressed in fetal chicken limbs, the conversion of proliferative to hypertrophic chondrocytes was delayed and expression of PTHrP was increased at the ends of the bones (Vortkamp et al 1996). Similarly, when an active fragment of sonic hedgehog (known to act like IHH in bone) was added to fetal mouse limb explants, chondrocyte differentiation was delayed and PTHrP expression was increased. In contrast, when the sonic hedgehog fragment was added to explants of limbs from either PTHrP~l~ or PTH/PTHrP receptor~!~ mice, no change in chondrocyte differentiation was seen. These results suggest that IHH acts to keep chondrocytes in the proliferative compartment by stimulating the synthesis of PTHrP. IHH is synthesized by prehypertrophic and early hypertrophic chondrocytes (Bitgood & McMahon 1995). The range of IHH action is limited, however, and it is not yet clear whether IHH directly stimulates

FIG. 1. Feedback loop involving PTHrP and IHH. PTHrP, secreted from perichondrial cells and chondrocytes near the end of the growth plate, delays the differentiation of chondrocytes that synthesize Ihh. Ihh, made by chondrocytes that have left the proliferative pool and have begun further differentiation, stimulates the synthesis of PTHrP.

FIG. 1. Feedback loop involving PTHrP and IHH. PTHrP, secreted from perichondrial cells and chondrocytes near the end of the growth plate, delays the differentiation of chondrocytes that synthesize Ihh. Ihh, made by chondrocytes that have left the proliferative pool and have begun further differentiation, stimulates the synthesis of PTHrP.

PTHrP synthesis or, instead, indirectly does so by activating a cascade of signalling molecules.

The interactions of PTHrP and IHH suggest that they participate in a negative feedback loop in the growth plate (Fig. 1). IHH is synthesized by cells just as they are leaving the proliferative compartment and turning on the hypertrophic cell programme. This IHH increases the synthesis of PTHrP, which then acts to delay the movement of chondrocytes from the proliferative to the hypertrophic compartments. Thus, PTHrP action delays the appearance of cells that synthesize IHH. The negative feedback loop involving PTHrP and IHH might be a way for the growth plate to sense the length of the proliferative columns and make local adjustments. This could assure coordination of the proliferation/differentiation of cohorts of cells within one growth plate, in the face of stochastic variations and multiple inputs from local and systemic factors. It is of interest, in this regard, that the PTHrP~/~ mice not only have short proliferative columns, but also have admixture of proliferative and hypertrophic cells within the same growth plate. In the absence of the postulated negative feedback loop, the coordination of chondrocyte differentiation is diminished.

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