1. Molecular Pathophysiology Musculoskeletal disorders – III Marie Kveiborg

2. Bone remodelling

3. Bone formation - osteoblasts

4. Osteoblasts functions: 1)Synthesis of most proteins of the bone matrix 2)Expression of genes necessary for calcification 3)Induction/downregulation of osteoclasts Osteoblast differentiation

5. Runx2 – a transcription factor essential for bone formation Komori et al. Cell 1997 Ducy et al. Cell 1997

7. Osteoblasts functions: 1)Synthesis of most proteins of the bone matrix 2)Expression of genes necessary for calcification 3)Induction/downregulation of osteoclasts Osteoblast differentiation

8. Osx +/ + Osx -/- Nakashima et al. Cell 2002

9. osteoclast

10. Osteoclast differentiation Preresorptive:1,25(OH) 2 vitamin D 3 ; PTH; PTHrP; PGE2; IL1; IL6; TNF etc. Anti-resorptive:estrogens; calcitonin; BMP2; BMP4; TGF  ; PDGF; calcium etc. Bone resorption [Ca 3 (PO 4 ) 2 ] 3 Ca(OH) 2 + 8H + 10Ca 2+ + 6HPO 4 2- + 2H 2 O

12. Bone remodelling

13. OPG/RANKL system Blair et al. Nature Clin Prac Oncol WT OPG -/- RANKL -/- RANK -/-

14. Bucay et al Genes Dev 1998 OPG-deficient mice OPG +/+ OPG -/-

16. 3 stages of NFATc1-mediated osteoclast differentiation (Nuclear Factor of Activated T-cells, calcineurin-dependent 1) Asagiri & Takayanagi, Bone 2007

17. Cooperation between RANKL and ITAM signals Asagiri & Takayanagi, Bone 2007

19. Copyright ©2006 American Society for Clinical Investigation Krishnan et al. J. Clin. Invest. 2006 Wnt/  -catenin signaling regulates osteogenesis through multiple mechanisms

20. Copyright ©2006 American Society for Clinical Investigation Elements of Wnt/  -catenin signaling Krishnan et al. J. Clin. Invest. 2006

24. Osteoporosis 30 years 60 years 60 years - osteoporotic

26. Therapies for osteoporosis Antiresorptive agents: –bisphosphonates (Ibandronate, Alendronate, Risedronate) –Selective estrogen response modulators (SERMs) (Raloxifene, Tamoxifen) –Denosumab (MAb to RANKL) – Phase III Calcium & Vitamin D supplementation Calcimimetics (CaR agonists – lowers PTH) Anabolic and combination therapies

27. Clinical trial – Denosumab (MAb RANKL) Schwartzman et al. N Engl J Med 2006

28. Bone metastasis Much more common than primary bone tumors Prostate, breast, lung, kidney cancer often metastasize to bone

29. Blair et al. Nature Clin Prac Oncol 2006 OPG & RANKL in cancer-bone interactions

30. Blair et al. Nature Clin Prac Oncol, 2006 Control Sham Vehicle-treated Tumor injection OPG-Fc-treated EarlyLateDelayed OPG-Fc inhibits osteolytic lesions of prostate cancer cells

31. Rheumatoid Arthritis

35. Copyright ©2007 by the National Academy of Sciences Ochi, Sae et al. (2007) Proc. Natl. Acad. Sci. USA 104, 11394-11399 Fig. 1. Promotive effects of TNF-{alpha} on RANKL-induced osteoclastogenesis and NFATc1 autoamplification

36. Copyright ©2007 by the National Academy of Sciences Ochi, Sae et al. (2007) Proc. Natl. Acad. Sci. USA 104, 11394-11399 Fig. 2. Selective induction of PIR-As and their ligands in response to TNF-{alpha} stimulation

37. Copyright ©2007 by the National Academy of Sciences Ochi, Sae et al. (2007) Proc. Natl. Acad. Sci. USA 104, 11394-11399 Fig. 3. Central role of PIR-As and their adaptor FcR{gamma} in enhanced osteoclastogenesis induced by TNF-{alpha}

38. Copyright ©2007 by the National Academy of Sciences Ochi, Sae et al. (2007) Proc. Natl. Acad. Sci. USA 104, 11394-11399 Fig. 4. FcR{gamma} mediates bone destruction and osteoporosis, but not inflammation in hTNFtg mice

39. Copyright ©2007 by the National Academy of Sciences Ochi, Sae et al. (2007) Proc. Natl. Acad. Sci. USA 104, 11394-11399 Fig. 4. FcR{gamma} mediates bone destruction and osteoporosis, but not inflammation in hTNFtg mice

40. Copyright ©2007 by the National Academy of Sciences Ochi, Sae et al. (2007) Proc. Natl. Acad. Sci. USA 104, 11394-11399 Fig. 5. Involvement of MHC class I molecules in TNF-{alpha}-induced bone loss

41. Copyright ©2007 by the National Academy of Sciences Ochi, Sae et al. (2007) Proc. Natl. Acad. Sci. USA 104, 11394-11399 Fig. 6. Infliximab normalizes enhanced osteoclastogenic potential and bone loss in hTNFtg mice