Molecules involved in regulation of osteoblast activity and osteoclast activity, and methods of use thereof

Abstract

The present invention is based, at least in part, on the identification of molecules involved in the differentiation and / or activity of osteoblasts and osteoclasts. Accordingly, the present invention provides methods of identifying modulators of bone formation, mineralization, and / or osteoclastogenesis and methods for treating disorders that would benefit from modulation of bone formation, mineralization, and / or osteoclastogenesis using agents identified as described herein. The target biomolecules of these methods are, for example, the osteoblast regulators TA0K2 or DLG1 or P1N1 or LYK5 or M0BKL2C or MAP4K2 or PACSIN2 or DCAMKLI or D0CK4 or PARO1 or TA0K3 or TRPV6 or CLK1 or AAK1 or PRKCA or AKAP8 or DGKJ or SMARCB1 or CIB2 or STIK33 or STK 39 or NRGN or PIK3R1 or RASSF5 or FRAPI or STK3S or LATSI or LATS2 or STK38L or GEFT or TNNI3K or STK4 or RAF1 or ARFI or CI7orf1 or SMURF2. The assays may involve mesenchymal cells. Also screening assays using osteoclast regulators such as GCK or WASH or PPP2CB or PPP2R1A or CREBBP or CUL3 or FBXW1 or MELK or PLCLI or MAP3K3 or DLGH1 or NEK7 or JIRAK3 or RHOC or SLC4A2 or PLCB4 or B-RAF or BMPR2 or MAPK3 or NHEDC2 are proposed, e.g. using hemapoietic stem cell assays.

Description

RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 60 / 932,101, filed May 29, 2007, titled “MOLECULES INVOLVED IN REGULATION OF OSTEOBLAST ACTIVITY AND OSTEOCLAST ACTIVITY, AND METHODS OF USE THEREOF”, the entire contents of which is incorporated herein by this reference.BACKGROUND OF THE INVENTION[0002]Bone is a dynamic tissue whose matrix components are continuously being remodeled to preserve the structural integrity of the skeleton. Bone remodeling is a cyclical process where under normal physiological conditions, bone formation occurs only at sites where bone resorption has previously taken place. Homeostatic remodeling of the skeleton is mediated primarily, if not exclusively, by the osteoclast and the osteoblast (Erlebacher, A., et al. (1995). Cell 80, 371-378). Osteoclasts are giant multinucleated cells of hematopoietic origin that are responsible for bone resorption. Osteoblasts, which originate from mesenchymal stem cells, synthes...

AI Technical Summary

Benefits of technology

The present invention is based on the identification of molecules involved in the differentiation and activity of osteoblasts and osteoclasts, which are cells responsible for bone formation and mineralization. The invention provides methods for increasing bone formation and mineralization by identifying compounds that regulate the expression and activity of these molecules. The invention also provides methods for identifying compounds that increase bone formation and mineralization by contacting indicator compositions with test compounds and evaluating their effect on the expression and activity of the osteoblast or osteoclast regulator. The invention also provides methods for identifying compounds that increase bone formation and mineralization by providing hematopoietic stem cells with an osteoclast regulator and evaluating the effect of test compounds on the regulator's activity. Overall, the invention provides a way to identify compounds that can promote bone growth and mineralization for therapeutic purposes.

Problems solved by technology

Currently available treatments for skeletal disorders and bone loss, whether targeted at bone formation by the osteoblast or bone resorption by the osteoclast, are inadequate.

The scarcity of knowledge about the molecular and cellular targets in these cell types hinders the discovery of new therapeutics.