Conversely, overexpression of PTHrP in chondrocytes leads to a delay in chondrocyte maturation and bone formation

Long bones develop by a process called endochondral bone formation, in which a cartilage model is generated and then is replaced with bone (Erlebacher et al., 1995; Cancedda et al., 1995). Endochondral development begins with condensation of undifferentiated mesenchymal cells that prefigure the future skeletal elements. In the core of these condensations, cells differentiate into chondroblasts, which secrete cartilage matrix. Mesenchymal cells surrounding the cartilage rudiment form the perichondrium. At a specific stage, which is unique to each element, chondrocytes progress through a program of cell proliferation, maturation and hypertrophy. Changes in the composition and properties of the cartilage matrix in the hypertrophic zone allow invasion by capillaries and the ultimate replacement of cartilage by the trabecular bone matrix secreted by invading osteoblasts. The rate of chondrocyte differentiation must be carefully regulated so that the proper shape and length of the bone is achieved and maintained. Several factors have been implicated in the regulation of endochondral bone formation. Parathyroid hormone-related peptide (PTHrP) is a secreted peptide expressed in a wide variety of adult and embryonic cell types, including osteoblasts and chondrocytes (Suva et al., 1987; Broadus and Stewart, 1994). The PTH/PTHrP receptor (PTHR) is also expressed in a wide range of cell types including a population of prehypertrophic chondrocytes in the growth plate (Karperien et al., 1994; Lee et al., 1995). The importance of PTHrP in endochondral bone formation is demonstrated in mice homozygous for a targeted disruption of the Pthrp gene (Pthlh – Mouse Genome Informatics). Pthrp-null mice demonstrate accelerated maturation of chondrocytes leading to excessive endochondral bone formation (Karaplis et al., 1994; Amizuka et al., 1994). Mice with targeted deletion of the Pthr demonstrated a similar phenotype (Lanske et al., 1996). Conversely, overexpression of PTHrP in chondrocytes leads to a delay in chondrocyte maturation and bone formation such that mice are born with a completely cartilaginous skeleton (Weir et al., 1996). Furthermore, mutations resulting in either a constitutively active or an inactive PTHR in humans result in 1913 Development 129, 1913-1924 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV9813