Northern Metabolic Bone Research Laboratory
Head of laboratory
On this page:
- Overview of research program
- Major funding source
- Selected publications
- Major collaborations
- Research project opportunities
Overview of research program
We are interested in studying the molecular and genetic bases of calcium, phosphate and vitamin D metabolism and their role in metabolic bone diseases such as osteoporosis, hyperparathyroidism and hypophosphataemic rickets. In detail, these programs consist of:
a) molecular and genetic regulation of vitamin D metabolism
The biologically active dihydroxylated metabolite of vitamin D (1,25-(OH)2D3) is formed by renal 1α-hydroxylation of circulating precursor 25-hydroxyvitamin D. The gene for the mitochondrial 1α-hydroxylase, CYP27B1 has recently been cloned. We have recently identified the novel association of intragenic polymorphisms within CYP27B1 and fractures in a cohort of elderly subjects. The significance of this research is the potential to identify patients at risk of developing osteoporosis, as well as identifying those patients for whom vitamin D therapy may be more effective.
b) molecular and genetic regulation of calcium metabolism
Calcium homeostasis is principally regulated by the action of hormones (PTH and vitamin D) on the intestine, bone and kidney. Calcium itself exerts negative feedback on the parathyroid cell via the G-protein-coupled calcium sensing receptor (CaSR). Inactivating mutations within the CaR gene have been associated with a disorder termed familial hypocalciuric hypercalcaemia (FHH). We have identified CaR gene mutations in 11 kindreds affected by FHH, including six novel mutations. One of these mutations (aspartate-to-glycine change at codon 216, D216G) is particularly interesting since it lies within a "hot spot" for mutations in this gene and possibly identifies a calcium-binding site within the receptor. In collaboration with A/Professor A Conigrave (School of Molecular and Microbial Biosciences, University of Sydney), structural modelling of this aspartate residue shows its location within a negatively-charged pocket of the receptor. We are now conducting functional studies of this mutation to determine its exact role in disturbing calcium-receptor interaction. This is the first time that a calcium-binding site has been identified within this receptor, and may potentially facilitate intelligent design of novel CaR-binding analogs. Modulation of CaR function by other agonists has recently been shown to have therapeutic value in treating hyperparathyroidism, and possibly osteoporosis.
c) molecular and genetic regulation of phosphate metabolism
The regulation of phosphate homeostasis has been poorly understood. Recently, mutations with the gene encoding fibroblast growth factor-23 (FGF-23) were associated with the inherited phosphate wasting disorder autosomal dominant hypophosphataemic rickets. Moreover, we have shown that serum FGF23 concentrations are elevated in the acquired phosphate wasting disorder oncogenic osteomalacia, and that FGF23 falls following successful removal of the tumour. We have recently studied the possible paracrine role of FGF23 within bone tissue itself. We have shown that cultured human osteoblasts respond to FGF23 by altering gene transcription of key vitamin D synthetic enzymes.
d) molecular and genetic regulation of purinergic receptors in osteoclasts and osteoblasts
We are collaborating with Professor J Wiley to investigate the possible role of purinergic receptors in skeletal homeostasis. The P2X7 receptor is a cation channel that responds to extracellular ATP. Expression of this receptor has recently been shown on the surface of osteoclasts. At this location, the P2X7 receptor may function to mediate signals from osteoblasts to osteoclasts and thus participate in the well-known coordination between bone formation and resorption. Professor J Wiley is internationally recognized for his work on P2X7 functional polymorphisms. We are now studying whether key P2X7 loss-of-function genotypes are associated with menopausal bone loss.
Major funding source
- Endocrine Trust Funds
Selected publications
Au AY, McDonald K, Gill A, Sywak M, Diamond T, Conigrave AD, Clifton-Bligh RJ. PTH mutation with primary hyperparathyroidism and undetectable intact PTH. N Engl J Med. 2008;359:1184-6.
Clifton-Bligh RJ, McElduff P, McElduff A. Maternal vitamin D deficiency, ethnicity and gestational diabetes. Diabet Med. 2008;25:678-84.
Elston MS, Stewart IJ, Clifton-Bligh R, Conaglen JV. A case of oncogenic osteomalacia with preoperative secondary hyperparathyroidism: description of the biochemical response of FGF23 to octreotide therapy and surgery. Bone 2007;40:236-41.
Stewart I, Roddie C, Gill A, Clarkson A, Mirams M, Coyle L, Ward C, Clifton-Bligh P, Robinson BG, Mason RS, Clifton-Bligh RJ. Elevated serum FGF23 concentrations in plasma cell dyscrasias. Bone. 2006;39:369-76.
Mun HC, Culverston EL, Franks AH, Collyer CA, Clifton-Bligh RJ, Conigrave AD. A double mutation in the extracellular Ca2+-sensing receptor's venus flytrap domain that selectively disables L-amino acid sensing. J Biol Chem. 2005;280:29067-72.
Nelson AE, Clifton-Bligh R, Miriams M, Gill A, Au A, Clarkson A, Juppner H, Ruff S, Stalley P, Scolyer RA, Robinson BG, Mason RS, Clifton-Bligh P. Clinical case seminar: Fibroblast growth factor 23: a new clinical marker for oncogenic osteomalacia. J Clin Endocrinol Metab. 2003;88:4088-4094.
Major collaborations
- Professor P Sambrook, Institute of Bone and Joint Research, Royal North Shore Hospital
- A/Professor A Conigrave, School of Molecular and Microbial Biosciences, University of Sydney
- Professor R Mason, Discipline of Physiology, University of Sydney
- Professor J Wiley, Department of Medicine, Nepean Hospital
Research project opportunities
Supervised by Dr Roderick Clifton-Bligh
