Physiological roles for parathyroid hormone-related protein: lessons from gene knockout mice.
A null mutation in the PTHrP gene produces profound abnormalities in endochondral bone formation in vivo. The role of PTHrP as a modulator of the chondrocytic proliferation and differentiation program is evident in the alterations that occur in its absence in the temporal and spatial sequence of chondrocyte development and subsequent endochondral bone formation that is necessary for normal bone elongation. These actions of PTHrP are probably responsible for the delay in chondrocyte development seen in Jansen osteochondrodystrophy, a disease caused by ligand-independent activation of the PTH-PTHrP receptor (Schipani et al., 1995). Furthermore, these conclusions have been corroborated by the observation that chondrocyte-specific overexpression of PTHrP causes a profound delay in the developmental program of chondrocyte differentiation and endochondral ossification (Weir et al., 1995). The morphological abnormalities in the knockout mice were limited to the skeletal system, despite the widespread production of PTHrP during fetal development. At this point, one can only speculate about the limited tissue distribution of the abnormalities. It is possible, for example, that other gene products, such as PTH, can compensate for the loss of PTHrP in some tissues. Alternatively, possible abnormalities in proliferation and differentiation may be present but morphologically subtle. A molecular assessment of these possible actions may well reveal more widespread effects of PTHrP.
Karaplis
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Division of Endocrinology, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Canada.
Kronenberg
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D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D002678:Chimera; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D044162:Parathyroid Hormone-Related Protein; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology*
D044162:Parathyroid Hormone-Related Protein; D011506:Proteins