St. Vincents Institute of Medical Research Fitzroy 3065, Victoria, Australia
Address correspondence and requests for reprints to: T. John Martin, M.D., St. Vincents Institute of Medical Research, 9 Princes Street, Fitzroy 3065, Victoria, Australia. E-mail: j.martin{at}medicine.unimelb.edu.au
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Introduction |
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Genetic studies in mice have revealed much more of the physiological roles of PTHrP. Mice rendered null for the PTHrP gene die very soon after birth, most likely from respiratory failure resulting from widespread abnormalities of endochondral bone development. Nonskeletal tissues and organs appear normal. Only when genetic "rescue" of the bone/cartilage phenotype was achieved in PTHrP-/- mice by using transgenes expressing either PTHrP under the control of a cartilage-specific promoter or constitutively active PTH/PTHrP receptor (PTHR1) did it become clear that PTHrP deficiency resulted in major defects in breast, skin, and tooth development.
The insights provided by these models obtained through mouse genetics provided the guidelines used by Wysolmerski et al. (1) in their morphological study of fetuses with Blomstrands chondrodysplasia, a rare syndrome resulting from loss-of-function mutations in the PTHR1 gene. Blomstrands chondrodysplasia is typified by short limbs, hypoplasia of the mandibles, advancement of skeletal maturation accompanied with ossification of the thyroid, and hyoid cartilages.
Mice rendered null for the PTHrP gene and rescued by transgenic expression of PTHrP in cartilage fail to develop mammary glands. This is the result of failure of branching morphogenesis, even though the first step in embryonic mammary gland development and formation of the mammary bud take place. The fetuses with Blomstrands chondrodysplasia lacked identifiable breast or nipple tissue. Thus, just as the evidence from mouse genetics has shown that PTHrP is essential to the formation of the embryonic mammary gland, this seems likely to be the case also in human embryonic breast development. In both mouse and human breast, PTHrP is expressed in epithelial cells and PTHR1 in mesenchymal cells, with the functional data suggesting strongly that PTHrP plays a crucial role in epithelial-mesenchymal signaling.
The finding in the Blomstrand fetuses of developing teeth severely impacted within the alveolar bone seems also to recapitulate the abnormalities in tooth development detected in PTHrP null mice. Careful analysis of the PTHrP-/- mice rescued by cartilage-directed PTHrP established that PTHrP is necessary for normal tooth eruption (2) and that this is due to failure of PTHrP-dependent osteoclast formation, the process necessary to form an eruption pathway (3).
Indeed, the mouse studies revealed a special role for PTHrP in regulation of osteoclast formation in the tooth microenvironment (3). There is no evidence for a generalized defect in osteoclast development in the PTHrP-/- mice (4). The tooth defects shown by Wysolmerski et al. (1) in Blomstrands chondrodysplasia consist of severe impaction, with resulting disordered architecture. They are the expected result as a consequence of lack of the resorption required to allow tooth eruption, and as is the case with the rescued PTHrP-/- mice and osteopetrotic mice. However, the tooth buds appear to have formed normally, and both amelogenesis and dentinogenesis are normal in Blomstrand fetuses. Furthermore, the distortion of the mandibular ramus in PTHrP null mice (5) is reminiscent of the craniofacial abnormalities noted in Blomstrands chondrodysplasia.
The genetic defect in Blomstrands chondrodysplasia results in inactivation of PTHR1, the G protein-coupled receptor that mediates the actions of the amino-terminal regions of both PTH and PTHrP (6). Mouse genetic studies have been highly informative in this area, identifying the crucial role of this signaling pathway, because inactivation of either the PTHrP or the PTHR1 genes results in severe skeletal deformities and defects in epithelial-mesenchymal transmission in breast, teeth, and skin.
The detailed studies carried out in mice take on greater significance when we are reassured, as in the study by Wysolmerski et al. (1), that the phenotype resulting from genetic ablation of the PTHR1 gene in the human fetus almost certainly is the same as that in the mouse. The implications are also that the local functions of PTHrP, studied so intensively in the mouse, are likely to be reflected in human physiology. It will certainly be of interest to determine whether the cardiovascular abnormalities of Blomstrands chondrodysplasia can lead us to any conclusions concerning the significance of the cardiovascular production and action of PTHrP.
Received February 14, 2001.
Accepted February 15, 2001.
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