Patent EP-1491895-A1 (EP)
Inventor: SCHUELE ROLAND PROF DR
IPC: G01N33/68
Filed: 2003-06-24
Abstract: Identifying a compound that promotes the activity of osteoblasts by contacting a cell with a test compound in vitro, determining the activity of a four and half LIM domains 2 (Fhl2) gene or Fhl2 protein, comparing the activity to that of a control cell not contacted with the compound, and selecting the compound if the measured activity is significantly different from that in the control cell. Identifying (M1) a compound that promotes the activity of osteoblasts, comprises: (a) contacting a cell with a test compound in vitro, determining the activity of a four and half LIM domains 2 (Fhl2) gene or Fhl2 protein in the cell, comparing the determined activity to the activity of Fhl2 gene or Fhl2 protein in a control cell that has not been contacted with the test compound, and selecting the test compound if the measured activity is significantly different from that in the control cell; or (b) administering a test compound to a transgenic non-human animal having a decreased level of expression of the Fhl2 gene relative to that of the corresponding wild-type animal, determining the activity of the Fhl2 gene or Fhl2 protein, comparing the determined activity to the activity of Fhl2 gene or Fhl2 protein in a control animal that has not been contacted with the test compound, and selecting the test compound if the measured activity is significantly different from that in the control animal. Independent claims are also included for the following: (1) a compound (I) that is useful in the treatment of a bone disease, where the compound is capable of promoting osteoblast activity by enhancing the expression of the Fhl2 gene, promoting the translocation of Fhl2 protein in the nucleus and/or modulating the interaction between Fhl2 protein and Runx2 protein; (2) use of an Fhl2 nucleic acid (II) for the manufacture of a medicament for the treatment of bone disease, where the Fhl2 nucleic acid is chosen from polynucleotides comprising a fully defined sequence of 840 nucleotides (S1) as given in the specification, polynucleotides comprising a sequence which has an identity of at least 50% to (S1), polynucleotides hybridizing to (S1) under stringent conditions, polynucleotides comprising a sequence encoding a polypeptide having a fully defined sequence of 279 amino acids (S2) as given in the specification, and polynucleotides comprising a sequence encoding a polypeptide having an amino acid sequence which has identity of at least 70% to the (S2); (3) diagnosing a bone disease comprising determining in vitro the level of expression of the Fhl2 gene in tissue from an individual, and comparing the determined level to the level of expression of the Fhl2 gene in control tissue, so that if the determined level is lower than that of the control, the individual is diagnosed as exhibiting the bone disease; and (4) use of transgenic non-human animal (III) having a decreased level of expression of the Fhl2 gene relative to that of the corresponding wild-type animal, as an osteoporosis model. ACTIVITY : Osteopathic. No supporting data is given. MECHANISM OF ACTION : Enhances Fhl2 gene expression (claimed).