Of Mice and Men, Recapitulation of Blomstrand’s Chondrodysplasia

T. John Martin and Matthew T. Gillespie

St. Vincent’s Institute of Medical Research Fitzroy 3065, Victoria, Australia

Address correspondence and requests for reprints to: T. John Martin, M.D., St. Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy 3065, Victoria, Australia. E-mail: j.martin{at}medicine.unimelb.edu.au


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When PTH-related protein (PTHrP) was discovered it was looked on as a hormone, secreted as it was by several cancers and causing hypercalcemia by its actions on bone to promote resorption and the kidney to reduce calcium excretion. It soon became apparent that PTHrP was produced in many tissues in the body, including skin, bone, blood vessels, and the uterus, where it exerts local biological actions that vary according to the location. Once sensitive assays for PTHrP were applied, it became clear that any PTHrP in the circulation postnatally was there at exceedingly low levels. Thus, the concept has developed that PTHrP is a paracrine and/or autocrine factor in many tissues of the body, functioning as a hormone when produced in excess by many cancers, but otherwise as a hormone only in the fetus, where it promotes calcium transfer across the placenta from mother to fetus.

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 Blomstrand’s chondrodysplasia, a rare syndrome resulting from loss-of-function mutations in the PTHR1 gene. Blomstrand’s 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 Blomstrand’s 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 Blomstrand’s 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 Blomstrand’s chondrodysplasia.

The genetic defect in Blomstrand’s 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 Blomstrand’s 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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  1. Wysolmerski JJ, Cormier S, Philbrick WM, et al. 2001 Absence of functional type 1 PTH/PTHrP receptors in human is associated with abnormal breast development and tooth impaction. J Clin Endocrinol Metab. 86:1788–1794.[Abstract/Free Full Text]
  2. Philbrick WM, Wysolmerski JJ, Galbraith S, et al. 1996 Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev. 76:127–173.[Abstract/Free Full Text]
  3. Nakchbandi IA, Weir EE, Insogna KL, Philbrick WM, Broadus AE. 2000 Parathyroid hormone-related protein induces spontaneous osteoclast formation via a paracrine cascade. Proc Natl Acad Sci USA. 97:7296–7300.[Abstract/Free Full Text]
  4. Suda N, Baba O, Udagawa N, et al. 1999 Disorganized intramembranous bone formation and analysis of osteoblasts and osteoclasts in PTHrP null mutant mice. J Bone Miner Res. 14:S292–F410.
  5. Shibata S, Suda N, Yamazaki K, et al. 2000 Mandibular deformities in parathyroid hormone-related protein (PTHrP) deficient mice: possible involvement of masseter muscle. Anat Embryol (Berl). 202:85–93.[CrossRef][Medline]
  6. Kronenberg HM, Lanske B, et al. 1998 Functional analysis of the PTH/PTHrP network of ligands and receptors. Recent Prog Horm Res. 53:283–301, discussion 301–303.[Medline]