Building bone to reverse osteoporosis and repair fractures
Sundeep Khosla, … , Jennifer J. Westendorf, Merry Jo Oursler
Sundeep Khosla, … , Jennifer J. Westendorf, Merry Jo Oursler
Published February 1, 2008
Citation Information: J Clin Invest. 2008;118(2):421-428. https://doi.org/10.1172/JCI33612.
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Building bone to reverse osteoporosis and repair fractures

Abstract

An important, unfilled clinical need is the development of new approaches to improve fracture healing and to treat osteoporosis by increasing bone mass. Recombinant forms of bone morphogenetic protein 2 (BMP2) and BMP7 are FDA approved to promote spinal fusion and fracture healing, respectively, and the first FDA-approved anabolic drug for osteoporosis, parathyroid hormone, increases bone mass when administered intermittently but can only be given to patients in the US for two years. As we discuss here, the tremendous explosion over the last two decades in our fundamental understanding of the mechanisms of bone remodeling has led to the prospect of mechanism-based anabolic therapies for bone disorders.

Authors

Sundeep Khosla, Jennifer J. Westendorf, Merry Jo Oursler

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Figure 3

A partial view of the canonical Wnt signaling pathway.

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A partial view of the canonical Wnt signaling pathway. Wnts bind a recep...
Wnts bind a receptor complex consisting of LRP5 or LRP6 and one of ten Fz proteins. This prevents phosphorylation of β-catenin by GSK3β and other kinases and its subsequent degradation. Of note, mutating the residues that can be phosphorylated to alanine creates stable, gain-of-function β-catenin proteins. Stabilized β-catenin accumulates and translocates to the nucleus, where it interacts with Tcf7 and related transcription factors (Lef1, Tcf7L1, Tcf7L2) to regulate gene expression. Outside the cell, molecules that sequester either LRP5 (e.g., Dkk1 and sclerostin) or the Wnt ligand (e.g., Sfrp) negatively control the canonical Wnt signaling pathway. Lithium chloride inhibits GSK3β inside the cell. APC, adenomatosis polyposis coli.