Compositions and Methods for Modulating Rank Activities

A nucleic acid encoding a RANK polypeptide comprising at least one mutation at an amino acid residue corresponding to an amino acid residue selected from the group consisting of I535, V536, V537, Y538, and any combination of the foregoing, of SEQ ID NO:2.

A chimeric polypeptide comprising an non-RANK extracellular domain and at least 20 contiguous amino acids of a RANK intracellular domain, comprising residues corresponding to amino acids 535-538 of SEQ ID NO:2.

A method for identifying a compound capable of modulating osteoclast cell differentiation, comprising:

• a) providing an osteoclast precursor cell comprising a receptor comprising a RANK polypeptide,
• b) contacting the osteoclast precursor cell with a test compound and a ligand for the receptor, wherein the test compound interacts with one or more amino acids corresponding to an amino acid residue of 535-538 of SEQ ID NO:2, and
• c) determining whether osteoclast formation has been modulated, said modulation being an indication that the compound modulates osteoclast cell differentiation.

A method for identifying a compound capable of modulating RANK activity, said method comprising:

• a) inducing oligomerization of a receptor comprising a RANK polypeptide in the presence or absence of a test compound, wherein the test compound interacts with one or more amino acids corresponding to an amino acid residue of 535-538 of SEQ ID NO:2, and
• b) detecting modulation of at least one RANK-mediated signaling pathway in said cell after said oligomerization, said activation level being an indication that the compound modulates activity of RANK.

A method for identifying a compound capable of modulating RANK activity, comprising:

• a) providing a cell comprising a receptor comprising a RANK polypeptide,
• b) contacting the cell with a test compound and a ligand for the receptor, wherein the test compound interacts with one or more amino acids corresponding to an amino acid residue of 535-538 of SEQ ID NO:2, and
• c) determining whether a RANK-mediated signaling pathway has been modulated, said modulation being an indication that the compound modulates RANK activity.

A method for identifying a compound capable of inhibiting RANK activity, said method comprising:

• a) inducing oligomerization of a chimeric transmembrane protein in an osteoclast precursor cell in the presence or absence of a test compound, said chimeric protein comprising a non-RANK extracellular domain and a RANK intracellular domain, wherein the test compound interacts with one or more amino acids corresponding to an amino acid residue of 535-538 of SEQ ID NO:2;
• and
• b) detecting activation level of at least one RANK-mediated signaling pathway in said cell after said oligomerization, wherein a reduction in the activity level in the presence of said molecule compared to that in the absence of said molecule is indicative of the ability of said molecule to inhibit RANK activity.

A method of improving bone mass in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound that decreases differentiation of a osteoclast precursor cell to an osteoclast, wherein the compound interacts with one or more amino acids corresponding to residues 535-538 of SEQ ID NO:2.

A method of improving bone mass in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound that inhibits the activity of RANK in an osteoclast cell, wherein the compound interacts with one or more amino acids corresponding to residues 535-538 of SEQ ID NO:2.