prehypertrophic cells, stimulates expression of parathyroid hormone (PTH)-related peptide (PTHrP) which negatively regulates terminal chondrocyte differentiation through the PTH/PTHrP receptor (PPR). However, the roles of PTHrP and Ihh in regulating earlier steps in chondrocyte

Developing murine growth plates comprise at least three morphologically distinct groups of chondrocytes (see Fig. 3C): round periarticular chondrocytes, flat columnar chondrocytes and hypertrophic chondrocytes. Periarticular chondrocytes proliferate and differentiate into columnar chondrocytes that proliferate further and form orderly columns. Unlike the round periarticular chondrocytes, the flat columnar chondrocytes form columns with clearly defined polarity; this polarity is particularly important in the asymmetric lengthening of the long bones of the limbs. These cells stop proliferating and then differentiate into non-proliferating hypertrophic cells. This sequential and synchronized differentiation is tightly controlled during endochondral bone development; consequently, sharp borders separate the exclusive domains of these three types of cells. One of the major regulators of this differentiation is parathyroid hormone (PTH)-related protein (PTHrP) expressed in the periarticular region. Both PTHrP null (Pthrp–/–; Pthlh – Mouse Genome Informatics) and PTH/PTHrP receptor (PPR) null (Ppr–/–; Pthr – Mouse Genome Informatics) mice develop chondrodysplasia because of premature hypertrophic differentiation (Karaplis et al., 1994; Lanske et al., 1996). The columnar layer is short in Pthrp–/– mice and virtually absent in Ppr–/– mice. PTHrP expression in the periarticular region depends upon and is upregulated by another factor that is crucial for cartilage development, Indian hedgehog (Ihh) (Vortkamp et al., 1996; Lanske et al., 1996; Chung et al., 1998; St-Jacque et al., 1999; Chung et al., 2001). In addition to stimulating PTHrP expression, Ihh expression is associated with PTHrPindependent chondrocyte proliferation (Karp et al., 2000). Previous studies using chimeric growth plates comprising wild-type and PPR-null cells have demonstrated that loss of PPR signaling in proliferating chondrocytes caused premature hypertrophic differentiation (Chung et al., 1998). However, Ppr–/– cells in the periarticular region of the chimeric growth plate are not morphologically distinct from wild-type cells. The 2977 Development 129, 2977-2986 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV3634