Yale Center for X-Linked Hypophosphatemia

 

RESEARCH PROJECTS

The role of parathyroid hormone in the pathogenesis of skeletal disease in X-linked hyphophosphatemic rickets (XLH)

Thomas Carpenter, Karl Insogna and Elizabeth Olear

 

 

 

 

 

 

 

 

XLH is the most common heritable form of rickets/osteomalacia in the US.  The disorder is characterized by renal phosphate wasting, rickets and limited growth in childhood. Osteomalacia and fractures occur in adults. At all ages and irrespective of treatment there is a high incidence of secondary hyperparathyroidism.  We hypothesize that elevated PTH levels may significantly contribute to the skeletal disease in XLH. We are presently conducting clinical studies that examine this idea in two ways. The first study, an observational one, provides a detailed characterization of the clinical features of XLH.  The study assesses skeletal disease burden using symptom questionnaires, height and height Z scores, numbers of lifetime and annualized number of fractures, number of osteotomies, number of dental abscesses, and the number and extent of exostoses and calcified enthesis, the latter assessed radiographically. The study protocol is conducted during a 24-hour admission to Yale's Clinical Research Center with diurnal monitoring of PTH, FGF-23 and serum phosphorus levels.  This monitoring occurs in the absence of concomitant therapy for the disease. The planned analyses will test the hypothesis that hyperparathyroidism significantly contributes to skeletal disease in XLH.  This is a cross-sectional study with a planned enrollment of 50 affected subjects and 20 controls.  We will examine radiographic changes with age. Disease severity will be studied in relationship to circulating levels of PTH and other potential mediators of the disease.  We are hopeful that this study will shed light on future directions of therapy in XLH.

Our second ongoing study proposes to use paricalcitol to suppress the secondary hyperparathyroidism that occurs in this condition. We hypothesize that long term correction of secondary hyperparathyroidism in XLH will be accompanied by a reduction in markers of bone turnover and symptomatic improvement in skeletal disease.  The study involves an initial overnight assessment at the Research Unit followed by a therapeutic intervention. After the overnight evaluation, subjects are randomized to either paracalcitol (Zemplar®), or placebo, and treated for a one year period, after which a repeat overnight evaluation is performed. If successful, this trial will provide proof of concept for the use of paricalcitol in the treatment of XLH.

If you have XLH, and are at least 9 years of age, you may be eligible to participate in either of these studies.  Please contact Danielle Frank  (danielle.frank@yale.edu) for further information if you are interested in participating.

 

Phosphate, PTH, and FGF23 as mediators of the rachitic growth plate

Marie Demay, M.D.

 

 

 

 

 

Marie Demay MD is an Associate Professor of Medicine at Harvard Medical School.  She is Director of the Endocrine Associates Practice and Associate Program Director for Basic Science Career Development in the Department of Medicine at the Massachusetts General Hospital.  Dr. Demay is a physician-scientist whose research has focused on the actions of 1,25-dihydroxyvitamin D and its receptor at the cellular, molecular and in vivo levels as well as investigating factors that modulate osteoblast differentiation.  Her interest in rachitic and hypophosphatemic disorders developed during her investigations in a mouse model of Hereditary Vitamin D Resistant Rickets engineered in her laboratory. Her investigations demonstrated that rickets in these Vitamin D Receptor knockout mice was a consequence of impaired apoptosis of hypertrophic chondrocytes and that hypophosphatemia plays a key role in the etiology of this growth plate abnormality.  Studies into the molecular basis for the actions of phosphate demonstrated that extracellular phosphate mediates apoptosis of primary murine hypertrophic chondrocytes by activating the mitochondrial apoptotic pathway.  Studies in the current proposal are focused on identifying the molecular basis for the differential susceptibility of proliferative and hypertrophic chondrocytes to phosphate-mediated apoptosis and on characterizing the effects of hormones and growth factors on modulating this process. These investigations will examine the effects of PTH, FGF23 and 1,25-dihydroxyvitamin D on phosphate-mediated hypertrophic chondrocyte apoptosis using in vitro and in vivo models. 

 

The structure, function, and pharmacologic inhibition of FGF23

Josephy Schlessinger, Ph.D.

 

 

 

 

 

FGFs mediate their biological responses by binding to and activating a family of receptor tyrosine kinases (RTKs) consisting of four gene products designated FGFR1-FGFR4. FGFR 1-3 have two isoforms produced by alternate splicing which differ in their ligand-binding specificities and tissue expression patterns.
FGF23 is the largest of the 22 known FGFs and differs from others by its unique extended C-terminal domain. XLH patients have elevated circulating levels of FGF23, and  heterozygous mutations within a protease recognition site in the FGF23 gene cause a syndrome that phenocopies XLH, autosomal dominant hypophosphatemic rickets (ADHR). In ADHR, resistance to proteolytic cleavage of the FGF23 molecule presumably leads to delayed clearance and accumulation in the circulation. Furthermore, tumor induced osteomalacia (TIO), another disorder with a similar phenotype to XLH, has been found to be caused in many cases by tumor overproduction of FGF23 as a paraneoplastic syndrome.

V.P. Eswarakumar, Ph.D.

 

 

 

 

 

 

Finally, recessive mutations resulting in low intact circulating FGF23 levels cause tumoral calcinosis (TC), an unusual disorder in which serum P levels are elevated.  Thus these clinical observations have ascribed a novel role for FGFs, and FGF23 in particular, in phosphate homeostasis. However, little is known about the mode of action of FGF23, and the potential for translating new information from exploring these pathways to human diseases is great. 
   

The overall goals of this project are (1) To determine the cell signaling function of FGF23 via FGF receptors, (2) To determine the atomic structure of FGF23, (3) To explore the receptor specificity of FGF23 using murine models deficient in specific FGFR isoforms, (4) To generate new mouse models to explore the biological function of FGF23 in normal and disease conditions, and (5) To develop new pharmacological approaches using small molecule inhibitors of FGFR tyrosine kinase domain for the treatment of diseases caused by abnormal FGF23 function. Our goals will be accomplished by applying genetic, biochemical, structural and cell biological approaches, in the setting of a model human disease in which to carry forward subsequent translational application.