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Gérard Friedlander , MD, PhD

OSTEOSCOOP WEBINAR Cellular regulators of bone remodeling in health and disease: a step to molecular medicine. Gérard Friedlander , MD, PhD. Growth factors. M-CSF augments RANKL-induced resorption in mature human osteoclasts. RANKL. Osteoclast. RANK. Cell differentiation.

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Gérard Friedlander , MD, PhD

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  1. OSTEOSCOOP WEBINARCellular regulators of bone remodeling in health and disease: a step to molecular medicine Gérard Friedlander, MD, PhD

  2. Growth factors

  3. M-CSF augments RANKL-induced resorption in mature human osteoclasts

  4. RANKL Osteoclast RANK Cell differentiation Pre-osteoclast Osteoclast Activation Bone resorption

  5. RANKL Osteoclast RANK Cell differentiation Pre-osteoclast + M-CSF + Osteoclast Activation 200 – 300% increase Bone resorption

  6. RANKL Osteoclast RANK Cell differentiation Pre-osteoclast + M-CSF + Osteoclast Activation 200 – 300% increase MEK-P ERK1/2-P c-fos Bone resorption favors Mature Osteoclast

  7. RANKL Osteoclast RANK Cell differentiation Pre-osteoclast + M-CSF + Osteoclast Activation 200 – 300% increase MEK P inhibitor PD98059 MEK-P ERK1/2-P c-fos Bone resorption favors Mature Osteoclast

  8. Epidermal Growth Factor Receptor plays an anabolic role in bone

  9. EGFR Osteoblast

  10. EGFR ligands HBEGF Epigen Amphiregulin Epiregulin Betacellulin TGF EGF EGFR Osteoblast

  11. EGFR ligands HBEGF Epigen Amphiregulin Epiregulin Betacellulin TGF EGF EGFR P P Osteoblast

  12. EGFR ligands HBEGF Epigen Amphiregulin Epiregulin Betacellulin TGF EGF EGFR P P Signaling pathways Osteoblast

  13. EGFR ligands HBEGF Epigen Amphiregulin Epiregulin Betacellulin TGF EGF EGFR P P Signaling pathways Osteoblast Reduced bone resorption Increased bone formation Increased bone volume and mineral density

  14. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells

  15. IGF-1 release Osteoblasts Osteoclasts Bone resorption Bone formation IGF-1

  16. Mesenchymal Stem cell Osteoblast differentiation Pre-osteoblast + mTOR Igf1r IGF-1 release Osteoblasts Osteoclasts Bone resorption Bone formation IGF-1

  17. Mesenchymal Stem cell Osteoblast differentiation Pre-osteoblast + mTOR Igf1r IGF-1 release Osteoblasts Osteoclasts Bone resorption Bone formation IGF-1 Young rat Low bone matrix IGF-1 Low bone formation IGF-1 Aged rat

  18. Mesenchymal Stem cell Osteoblast differentiation Pre-osteoblast + mTOR Igf1r IGF-1 release Osteoblasts Osteoclasts Bone resorption Bone formation IGF-1 Young rat Low bone matrix IGF-1 Low bone formation Higher bone matrix IGF-1 Higher bone formation IGF-1 + IGFBP3 IGF-1 IGF-1 Aged rat Aged rat

  19. Signaling pathways

  20. Physiological function of the Angiotensin AT1a receptor inbone remodeling

  21. Kidney Pre-osteoblast Renin ACE AT1a Liver Angiotensinogen Angiotensin I Angiotensin II Massive bone resorption

  22. Kidney Pre-osteoblast Renin ACE AT1a Liver Angiotensinogen Angiotensin I Angiotensin II Pre-osteoblast Massive boneresorption AT1a Increase bone mass

  23. Kidney Pre-osteoblast Renin ACE AT1a Liver Angiotensinogen Angiotensin I Angiotensin II Pre-osteoblast AT1a Massive boneresorption AT1a Osteocyte Increase bone mass RANKL OPG Sclerostin Osteoblasts Osteoclasts Bone Resorption Bone formation

  24. Osteoblast extracellular Ca2+ sensing receptor regulates bone development, mineralization and turnover

  25. Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ CaR Pre-osteoblast

  26. Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ CaR Pre-osteoblast WT CaR KO • Lower trabecular bone volume • Higher cortical bone porosity • Altered mineralization • Lower BMD • Smaller and lighter mouse • Frequent fractures • Died at 3-4 weeks old

  27. Ca2+ Ca2+ Ca2+ Ca2+ Altered osteoblast differentiation Affect bone formation and bone mineralization OPG CaR Ca2+ CaR NPP1 RANKL ANK OPN Pre-osteoblast RANKL Favors bone resorption RANK Pre-osteoclast WT CaR KO • Lower trabecular bone volume • Higher cortical bone porosity • Altered mineralization • Lower BMD • Smaller and lighter mouse • Frequent fractures • Died at 3-4 weeks old

  28. Targeting osteoclast – osteoblast communication

  29. Osteoclast progenitor Bone marrow mesenchymal cell Osteoclast precursor Pre-osteoblasts Osteoblasts Osteoclasts Osteocytes BONE RESORPTION BONE FORMATION

  30. RANKL Osteoclast progenitor Bone marrow mesenchymal cell RANK Osteoclast precursor Pre-osteoblasts OPG Osteoblasts Osteoclasts Osteocytes BONE RESORPTION BONE FORMATION

  31. RANKL Osteoclast progenitor Bone marrow mesenchymal cell RANK Osteoclast precursor Pre-osteoblasts OPG TGF-b1 Induce migration Osteoblasts Osteoclasts Osteocytes BONE RESORPTION BONE FORMATION

  32. RANKL Osteoclast progenitor Bone marrow mesenchymal cell RANK Osteoclast precursor Pre-osteoblasts OPG TGF-b1 Induce migration Sema4D Plexin B1 Osteoblasts Osteoclasts Osteocytes BONE RESORPTION BONE FORMATION

  33. Regulation of RANKL-induced osteoclastogenesis by TGF-b through molecular interaction between Smad3 and Traf6

  34. TGF-b TGF-b receptor RANKL RANK TAB1 TAB2 TAK1 TRAF6 TRAF6 TAB2 TAK1 TAB1 Osteoclastogenesis JNK JNK-P MAP38 MAP38-P

  35. TGF-b MH2 Smad3 Smad2 TGF-b receptor Smad3/Smad2/Smad4 RANKL RANK TAB1 TAB2 TAK1 TRAF6 TRAF6 TAB2 TAK1 TAB1 Osteoclastogenesis JNK JNK-P MAP38 MAP38-P

  36. TGF-b MH2 Smad3 Smad2 TGF-b receptor Smad3/Smad2/Smad4 RANKL RANK TAB1 TAB2 TAK1 Smad3/Smad2/Smad4 TRAF6 TRAF6 TAB2 TAK1 TAB1 Osteoclastogenesis JNK JNK-P MAP38 MAP38-P

  37. Overexpression of Secreted Frizzled-Related Protein 1 Inhibits Bone Formation and Attenuates Parathyroid Hormone Bone Anabolic Effects

  38. Wnt Enhanced osteoblast differentiation Frizzled -catenin PTH PTH-R

  39. sFRP 1 Wnt Enhanced osteoblast differentiation Frizzled -catenin PTH PTH-R

  40. sFRP 1 Wnt Enhanced osteoblast differentiation Frizzled X -catenin PTH Osteopenia PTH-R

  41. sFRP 1 Wnt Enhanced osteoblast differentiation + Frizzled X -catenin PTH Osteopenia PTH-R

  42. sFRP 1 Wnt Enhanced osteoblast differentiation + Frizzled X X -catenin PTH Osteopenia PTH-R

  43. A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

  44. BMP2/4 BMPR1A Smad1 P Smad4 P Smad5 Smad8 P Pre-osteoblast

  45. BMP2/4 BMPR1A-mFC mFC Osteoblasts Increase osteoblast differentiation BMPR1A Increasebone formation Smad1 P Smad4 P Smad5 Smad8 LowDKK1 P Pre-osteoblast

  46. BMP2/4 BMPR1A-mFC mFC Osteoblasts Increase osteoblast differentiation BMPR1A Increasebone formation Smad1 P Smad4 Pre-osteoclast P Smad5 Smad8 Decrease osteoclast differentiation LowDKK1 P Osteoclast LowRANKL Decrease bone resorption Pre-osteoblast

  47. BMP2/4 BMPR1A-mFC mFC Osteoblasts Increase osteoblast differentiation BMPR1A Increasebone formation Smad1 P Smad4 Low bone mass Pre-osteoclast P Smad5 Smad8 Decrease osteoclast differentiation LowDKK1 P Osteoclast LowRANKL Decrease bone resorption Pre-osteoblast BMPR1A-mFC Increase bone mass Ovx mouse

  48. Local mediators and regulatory proteins

  49. EP1−/− mice have enhanced osteoblast differentiation and accelerated fracture repair

  50. Arachidonic acid PGE2 COX-2

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