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Targeting LRP5 to Increase Bone Formation in Osteoporosis

Objective

The balance between bone resorption and bone formation determines the mass and structural integrity of the skeleton and is disturbed in osteoporosis. In contrast to the molecular mechanisms regulating bone resorption, knowledge of the mechanisms regulating bone formation is limited. A recent breakthrough has been the identification of a link between bone mass in humans with rare bone disorders and gain- or loss-of function mutations of the Wnt co-receptor LRP5 or the Wnt antagonist sclerostin. The mechanism, however, underlying these actions on Wnt signalling is unclear. We propose studies with the following specific aims: i) to characterize the clinical, bioschemical, radiological and histological features of patients with sclerosteosis, van Buchem disease and other craniotubular hyperostoses ii) to determine the genetic defect in patients with craniotubular hyperostoses and establish putative genotype-phenotype correlations iii) to unravel the molecular mechanism of the inhibitory action of sclerostin on bone formation and to determine how genetic variations in SOST, LRP5 and Wnt signalling pathway modify bone architecture and remodelling iv) to reveal the pattern of sclerostin expression by analysis of the SOST promoter and by histomorphometry of human bone biopsies v) to identify and characterize co-factors of the LRP5 signalling and their in vivo actions in relevant animal models vi) to identify epitopes in sclerostin that mediate the interaction with LRP5, raise peptide-bound protein mimics and test them in vitro and in animal models of bone loss. These studies will not only help understanding the molecular basis of critical signalling pathway in bone formation but will also provide insight into normal and disturbed modulation of bone remodelling. Moreover, they will help in the design of bone forming interventions for the treatment of patients with osteoporosis.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation

Call for proposal

FP7-HEALTH-2007-A
See other projects for this call

Funding Scheme

CP-FP - Small or medium-scale focused research project

Coordinator

ACADEMISCH ZIEKENHUIS LEIDEN
Address
Albinusdreef 2
2333 ZA Leiden
Netherlands
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 831 950
Administrative Contact
Daan Katchaki (Mr.)

Participants (8)

UNIVERSITEIT ANTWERPEN
Belgium
EU contribution
€ 276 400
Address
Prinsstraat 13
2000 Antwerpen
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Anne Adams (Ms.)
THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE
United Kingdom
EU contribution
€ 295 754
Address
Trinity Lane The Old Schools
CB2 1TN Cambridge
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Dawn Barker (Ms.)
JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Germany
EU contribution
€ 277 000
Address
Sanderring 2
97070 Wuerzburg
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Christian Gloggengieser
UNIVERSITE DE GENEVE
Switzerland
EU contribution
€ 384 400
Address
Rue Du General Dufour 24
1211 Geneve
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Yvan Seguin (Mr.)
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
EU contribution
€ 226 000
Address
Rue De Tolbiac 101
75654 Paris
Activity type
Research Organisations
Administrative Contact
Dina Ramamonjisoa
PEPSCAN THERAPEUTICS BV
Netherlands
EU contribution
€ 222 400
Address
Zuidersluisweg 2
8243 RC Lelystad
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Ward Langendijk
PERCUROS BV
Netherlands
EU contribution
€ 222 400
Address
Plesmanlaan 1
2333 BZ Leiden
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Richard Plasek (Mr.)
MORPHOSYS AG
Germany
EU contribution
€ 168 000
Address
Lena Christ Stasse 48
82152 Martinsreid Planegg
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Klaus De Wall