Research Interests |
The research in this group is aimed at increasing
our understanding of the molecular bone-renal mechanisms that maintain
a healthy mineralized skeleton and dentition. Since this dynamic-process
is disturbed dramatically in many tumor-acquired and inherited diseases
we are also studying these diseases in the hope that our findings
will help to improve clinical treatment. In collaboration with an
international consortium (HYP-consortium) we successfully identified
the primary gene defect in an inherited bone-renal disease, X-linked
hypophosphatemic rickets (HYP). This disease is characterized by
severe under-mineralization of the skeleton and marked changes in
renal-phosphate handling and vitamin D metabolism. We named this
novel gene PHEX (acronym: phosphate regulating gene with homologies
to endopeptidases on the X-chromosome). This discovery has stimulated
new research and provided new reagents aimed at unraveling the molecular
pathways downstream of the primary PHEX gene-product defect. More
recently, we were the first to characterize and clone a completely
novel bone-matrix protein (MEPE) from patients with tumor-induced
osteomalacia. Also, we have demonstrated biological activity of
this new MEPE protein and confirmed a direct interaction with PHEX.
Our research indicates that a small acidic, protease-resistant MEPE-peptide
that we named ASARM-peptide, could potentially be the first ‘biological
bisphosphonate’ described. This peptide occurs in MEPE and
some related family proteins (SIBLINGs) and the acronym ASARM stands
for acidic-serine-aspartate-rich-MEPE-associated motif. The biological
and physicochemical properties of the ASARM-peptide are remarkably
similar to etidronate, a bisphosphonate. The ASARM-peptide (like
etidronate) inhibits mineralization in-vivo and in-vitro and impacts
on renal phosphate handling. Our research confirms ASARM-peptides
play a major role in regulating mineralization, bone resorption
and renal calcification. |