Key and Emerging Concepts in Bone Biology

1. Key and Emerging Concepts in Bone Biology • Developmental regulation of the growth plate • Remodeling of bone, coupling, and OPG/RANKL • Uncoupling • Mineral homeostasis • Role of inflammation in post-natal bone formation • Bone-fat interactions and reciprocity • Mechanical loading & skeletal transduction • Wnt signaling in the control of bone formation • Circulating osteogenic precursor cells • Age-related bone loss

2. BMD Scores in a Family with High Bone Mass Little, RD et al., Am. J. Hum. Genet. 70: 11-19 (2002)

3. BMD Scores in a Family with High Bone Mass Little, RD et al., Am. J. Hum. Genet. 70: 11-19 (2002)

4. High Bone Density Due to a Mutation in LDL-Receptor-Related Protein 5 Boyden, LM et al., NEJM 346: 1513-21 (2002)

5. Canonical Wnt/β-catenin signaling pathway • Extracellular binding of Wnt to the Fz–LRP5/6 receptor complex causes intracellular accumulation of β-catenin that can induce the expression of target genes after translocation to the nucleus. • In the presence of Dkk and Krm a tertiary protein complex can be made with LRP5/6 for internalization, thus inhibiting wnt signaling (β-catenin will no longer be stabilized but will be phosphorylated and subsequently degraded). • The extracellular sclerostin prevents further signaling by binding to LRP5/6–Fz .

6. HBM mutation and domain structure of the LRP5 protein Little, RD et al., Am. J. Hum. Genet. 70: 11-19 (2002)

7. D Mutations in LRP5/6 that prevent binding of Wnt signaling inhibitors cause a high bone mass phenotype

8. Mutations in LRP5 cause a spectrum of bone mass phenotypes

9. Wnt signaling in the control of bone formation • Key concept(s): • Wnt/β-catenin are key signaling molecules in osteoblastogenesis • Clinical correlates: • High & low bone mass syndromes • Osteoporosis pseudoglioma • Dwarfism • Van Buchem disease • Sclerotosis • Multiple targets for anabolic therapies