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CHAPTER IV

CHAPTER IV. Other osteopathies. Other osteopathies. 57. New susceptibility loci in Paget’s disease of bone. The presence of sequestosome mutations in familial or sporadic formes of Paget ‘s disease is well known Results of a large genomic study Loci other than the sequestosome (SQSTM1) ?

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CHAPTER IV

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  1. CHAPTER IV Other osteopathies

  2. Other osteopathies 57 New susceptibility loci in Paget’s disease of bone • The presence of sequestosome mutations in familial or sporadic formes of Paget ‘s disease is well known • Results of a large genomic study • Loci other than the sequestosome (SQSTM1) ? • 750 patients with Paget’s disease (without SQSTM1 mutation) • 2 699 control • Replicated data in 500 patients with Paget’s disease and 535 controls Sporadic forms Familiar forms 60 40 % 40 Patients with the SQSTM1 mjutation (%) 20 11 % 0 • M-CSF, DC-STAMP, RANK: key role in osteoclast differentiation • Optineurin function not yet elucidated • This study identifies 4 new susceptibility loci and reinforces the interest of the genetic approach for the comprehension of Paget’s bone disease pathogeny ASBMR 2010 - D’après Albagha O et al., Édimbourg, Royaume-Uni, abstr. 1031, actualisé

  3. Crossbreed of TRAP-MVP mice (expressing the nucleocapsid of measles virus) and developing morphological anomalies in osteoclasts (OC), with p62P394-Ki mutated mice, carriers of a SQSTM1 mutation that develops only functional anomalies of OC [hypersensibility to RANK and 1,25(OH)2D] Results Association of the mutation of SQSTM1 with nucleocapsid of the measles virus produces pagetoid localized lesions in mice Other osteopathies 58 Paget’s disease: role of the sequestosome mutation and of measles virus. Towards a murin model ? The p62KI/MVNP mice develop pagetoid bone lesions Controls p62KI/MVNP ( TRAP Coloration) • this model seems to reconciliate the genetic and viral hypothesis… ASBMR 2010 - D’après Kurihara N et al., Pittsburgh, États-Unis, abstr. 1032 actualisé

  4. Other osteopathies 59 Circulating osteogenic cells and nonhereditary heterotopic periarticular ossification (NHPO) • Circulant osteogenic precursors (COP), derived from the bone marrow, associated with heterotopic ossifications of the progressive ossifying fibrodysplasia • The authors demonstrate that the COP contribute also to the formation of periarticular NHPO after CNS injury, medullary trauma, cranial trauma and after arthoplasty • immunohistochemistry study of postchirurgical bone pieces: coexpression of type I collagen and of CD45 • association between the COP and early fibroproliferative and neovascular stages of OH • MO/COP in the regions without HO( heterotopic ossification) Formation stages of OHNH Extraskeletic soft tissue Lymphocytic perivascular Infiltration Soft tissue Infiltration Fibroproliferation Injury Heterotopic bone Coll I CD45 Damaged tissue release Early stages Endochondral bone formation CXCR4 Mature bone Cartilage formation Neovascularization COP osteogenic precursors Inflammatory cytokines migration (SDF-1, BMP4) Étapes tardives ASBMR 2010 - D’après Egan K et al., Philadelphie, États-Unis, abstr. 1013, actualisé

  5. 7 patients XLH and 6 controls Discontinuation of all therapies 2 weeks before the study 200 UI of salmon calcitonin intradermal Dosages of serum levels of GF-23, phosphatemia, calcemia, PTH, 1,25(OH)2 D3 for the following 26 hours Other osteopathies 60 Serum levels of FGF-23 after calcitonin (CT) injection in carriers of X-linked hypophosphatemia (XLH) 75 150 55 125 FGF-23 (pg/ml) Phosphatemia change (%) 100 35 75 15 50 -2 4 10 18 21 24 26 -2 4 10 18 21 24 26 Duration (hours) Duration (hours) 200 150 175 130 150 Changes in 1,25 (OH)2D3 (%) Changes in PTH(%) 110 125 90 100 70 75 -2 4 10 18 21 24 26 -2 4 10 18 21 24 26 Duration (hours) Duration (hours) • CT injection reduces rapidly serum levels of FGF/23 ; this reduction will be maintained for 16 hours. No FGF/23 modification in the control group • Comparable increase of 1.25 (OH)2 D3 levels in the 2 groups • Significant increase of phosphatemia and of TmP/GFR in the XLH group • CT : future treatment for XLH ? ASBMR 2010 - D’après Liu E et al., New Haven, États-Unis, abstr. FR0146, actualisé

  6. Before traitement 12 weeks Other osteopathies 61 A promising enzymatic treatment for hypophosphatasia • Hypophosphatasia:  activity of TNSALP (Tissue-Non Specific Alkalin Phosphatase) • accumulation of inorganic pyrophosphate , mineralization inhibitor • rickets • Open label, phase II study • ENB-0040: human recombinant fusion proteinof TNSALP • 13 children (2 boys, 11 girls, 5-12 years) • 2 to 3 mg/kg s.c. 3 x /week for 24 weeks • At 6 months • Treatment well tolerated •  alkaline phosphatase activity • Absence of hypocalcemia (no "hungry bone") •  disease markers (PPi, PLP) • Improvement of radiographic aspects • motricity, force, and agility improvement •  of pain and disability Serum alkaline phosphatase 16 000 14 000 12 000 10 000 8 000 U/l 5 613 5 493 5 253 4 338 6 000 4 000 2 000 45 0 Initial level w6 w12 w18 w24 • The ENB-0040 is a promising treatment for hypophosphatasia in children ASBMR 2010 - D’après Greenberg CR et al., Saint-Louis, États-Unis, abstr. 1016, actualisé

  7. Other osteopathies 62 Use of teriparatide in severe periodontitis • Objective: to evaluate the effect of teriparatide (PTH1-34), in addition to periodontal surgery, in patients with severe periodontitis • Randomized, monocenter, double-blind, placebo-controlled study • 40 patients without osteoporosis: surgery • 20 (9 ♂,11 ♀, 48 years [30-61]): + PTH1-34 20 µg/j injection + 1 g calcium and 800 UI vit. D/j for six weeks • 20 (6 ♂,14 ♀, 57 years [31-65]): + placebo injection+ 1 g calcium and 800 UI vit. D/j for six weeks • Follow-up: 12 months 1,86 mm+ 0,31 mm 2,42 mm+ 0,33 mm 1,58 mm+ 0,42 mm 2,4 2,5 3,2 Teriparatide 2,8 2,0 Teriparatide 2,0 Teriparatide 2,4 1,6 1,5 Bone gain (mm) 1,32 mm+ 0,37 mm 2,0 1,2 1,0 Reattachment level gain (mm) Periodontal pocket depth reduction (mm) 0,42 mm+ 0,29 mm 0,16 mm+ 0,24 mm 1,6 Placebo 0,8 Placebo 0,5 1,2 Placebo 0,4 0,8 0 Month 0 Month Month 0 0 0 3 6 1,5 3 6 0 1,5 3 6 9 12 9 12 9 12 • 6-week of teriparatide treatment combined with surgical treatment improves the clinical and radiological parameters of periodontitis at 12 months ASBMR 2010 - D’après Bashutski (1018)

  8. Other osteopathies 63 Treatment of mammary bone metastasis in rats with anti-IL-6R (tocilizumab) antibodies Osteolysis MR16-1 +tocilizumab 2,5 Tocilizumab Placebo MR16-1 2 1,5 MR16-1 +tocilizumab Jour 21 Tocilizumab Placebo MR16-1 Surface of the cortical bone (mm²) 1 0,5 0 Tumoral bud 7 Jour 21 6 5 T : tumor BM : bone marrow 4 Tumoral surface (mm²) 3 2 1 • Antibody anti-IL-6R treatment results in a reduction of the osteolysis and in a reduction of the tumor progression • IL-6 is a potential target in breast cancer treatment 0 Placebo Tocilizumab MR16-1 + tocilizumab MR16-1 ASBMR 2010 - D’après Boernert K et al., Sydney, Australie, abstr. FR0133, actualisé

  9. Other osteopathies 64 Activation of Notch pathway and osteosarcomas Notch pathway Osteomas Osteosarcomas Nucleus Delta, Jagged Notch PS1, PS2 Control NICD • Telangiectasias • Osteoid tumor • Osteoblastic cells wrongly differentiated • Necrosis • Hemorrhage MAML NICD BRJK Nucleus • Permanent activation of the Notch pathway is rapidly accompanied by the emergence of multiple osteomas • Old animals develop osteosarcomas • Notch represents a new therapeutic target for osteosarcomas ASBMR 2010 - D’après Tao J et al., Houston, États-Unis, abstr. FR0135, actualisé

  10. Prerequisites adiponectin (ADPN) deficient mices have a more agressive form of multiple myeloma evolution of patients with a MGUS and a low level of ADPN tends more towards a MM than patients with more elevated ADPN levels  ADPN induces the apoptosis of myeloma cells Objective: effect of increased ADPN levels on the development of MM in vivo Design: 4-week treatment of C57Bl/KaLwRij mice with L-4F, ADPN mimetic peptide , then inoculation of 5TGM1 myeloma cells.. L-4F is maintained through the end of experiment Other osteopathies 65 Role of adiponectin in myelomas Placebo L-4F 12 Number of lytic lesions 100 10 *p < 0,01 versus placebo 25 p < 0,001 8 Placebo 20 Serum concentration in IgG2b (mg/ml) 6 15 * 50 Survival (%) 10 4 L-4F 5 * 2 0 p < 0,0001 L-4F Placebo 0 0 0 10 20 30 0 10 20 30 Days • In vitro, L-4F has not a direct effect on myeloma cell growth but directly induces ADPN expression per stromal cell in bone marrow • This study indentifies ADPN and L-4F as potential therapeutic approaches ASBMR 2010 - D’après Fowler J et al., Nashville, États-Unis, abstr. 1085, actualisé

  11. Total OPN MMP7 OPN cleavage MMproliferation MMapoptosis Other osteopathies 66 Role of metalloproteinase (MMP)-7 in myeloma • Prerequisites : elevated MMP7 level is correlated to a tumoral invasion and to survival in different types of solid cancer • Hypothesis : MMP7 increases myeloma development in vivo** • Mice myeloma C57Bl/Rag2-/- MMP7-/- ***p < 0,001 *** 300 *** ** 12 Control + MM **p <0,01 16 MMP7-/- + MM 200 12 **p < 0,01 ***p < 0,001 8 Number of bon lesions Taux sériques d’ostéopontine(ng/ml) Controls *** Serum IgG2b (mg/ml) 8 MMP7 -/- 100 4 4 ** 20 0 0 0 2 4 Controls MMP7 -/- Controls 5TGM1 MM Duration as of inoculation of myeloma cells (weeks) • Osteopontin (OPN) is increased in myelomas, with different biological functions, according to its size • The long form increases proliferation of myeloma cells • The truncated form favors apoptosis of myeloma cells • MMP7 cleaves osteopontin and would favor apoptosis of myeloma cells ASBMR 2010 - D’après Lynch C et al., Nashville, États-Unis, abstr. 1086, actualisé

  12. SMO Shh Hh Gli2 PTCH1 Gli2 Act Activation Cyclin D, Cyclin E, MycGit1, Patch Gli2 Act Nucleus Cytoplasm Other osteopathies 67 Degenerative disc disease: blame the hedgehog ! Hedgehog pathway • Fundamental role of the hedgehog pathway and the Gli2 transcription factor in the spine formation 18 days 2 months Wild Gli2f/f mice Gli2-deficient miceGli2f/f; Col2CreER • After deletion of Gli2, a rapid destruction of intervertebral disc and a vertebral fusion are observed • Hedgehog pathway plays an essential role in degenerative disc disease ASBMR 2010 - D’après Zeng F et al., Rochester, États-Unis, abstr. 1121, actualisé

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