Date of Award


Document Type

Dissertation - Restricted

Degree Name

Doctor of Philosophy (PhD)


Biological Sciences

First Advisor

Ralph A. Meyer, Jr.

Second Advisor

Bela E. Piacsek

Third Advisor

Howard M. Klitgaard

Fourth Advisor

Gail L. Waring

Fifth Advisor

Nelson D. Horseman


X-1 inked hypophosphatemia (XLH) is the most common form of vitamin D-resistant rickets. Transmission of this human disease is by X-linked dominant inheritance. XLH is characterized by elevated renal excretion of phosphate, low plasma phosphate (hypophosphatemia) and osteomalacic bone disease. The most common clinical manifestation is short stature. Craniofacial abnormalities are also known to be a common physical, characteristic of the disease. Experiments designed to investigate the bone disease were performed on the X-linked hypophosphatemic (Hyp) mouse, which is a model for the human disease XLH. A longitudinal serial cephalometric and radiographic study was performed on normal and Hyp mice from 1 to 12 weeks of age. It was found that longitudinal growth is
deficient in the Hyp mice as early as one week of age. The Hyp mice exhibited shorter skulls anteroposteriorly and a compressed upper face height when compared to normal mice. A shorter nasal bone was the earliest abnormality seen in the Hyp mice. This appeared at week one and was the most important variable adding to the overall difference in skull morphology between Hyp and normal mice. The fronto-nasal suture and the premaxillary-maxillary suture in the Hyp mice were grossly deformed. In the meantime whole skeleton radiographs have revealed an unexpected transitory metaphyseal radio-opacity in the long bones of the young ~mice. This was present at the first week, peaked at the third week, and started to fade by the fourth week. Undecalcified bone sections of 3 week old mice showed an increased amount of trabecular bone in the metaphysis of the Hyp mice. In an attempt to elucidate the mechanisms underlying this phenomenon further experiments were performed. An understanding of the disease progression could elucidate the pathogenesis of the disease. A histomorphometric, histochemical, electron microscopic and ·biochemical study was conducted. It was found that young Hyp mice suffer from defective osteoclastic activity. Bone formation activity was accelerated in the young Hyp mice (10 days of age). A reduction in bone formation activity was seen by 30 days of age and continued through 91 day old mice. It is concluded that the increase in metaphyseal bone mass seen in the Hyp mice is due to both increased bone formation in the young Hyp mice and decreased bone resorption activity. At all ages Hyp mice had a greater amount of trabecular bone mass. However adult Hyp mice did not show the transitory metaphyseal radio-opacity seen in young Hyp mice. Because adult Hyp mouse bone also had a greater amount of inactive osteoid, this suggests that the bone is less mineralized and therefore relatively radiolucent. In order to elucidate the factor causing this variable morphologic picture, both plasma parathyroid hormone (PTH) levels and the effect of injecting PTH in Hyp and normal mice were investigated. It was found that intact young Hyp mice have a significantly elevated plasma PTH. Normal mice injected with PTH showed a biochemical and morphologic characteristic similar to vehicle treated Hyp. These data suggest that PTH may play an important role in the pathogenesis of the bony disease in the Hyp mice.



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