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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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Chapter iv

CHAPTER IV

Other osteopathies


New susceptibility loci in paget s disease of bone

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


Paget s disease role of the sequestosome mutation and of measles virus towards a murin model

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


Circulating osteogenic cells and nonhereditary heterotopic periarticular ossification nhpo

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


Serum levels of fgf 23 after calcitonin ct injection in carriers of x linked hypophosphatemia xlh

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


A promising enzymatic treatment for hypophosphatasia

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


    Use of teriparatide in severe periodontitis

    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)


    Treatment of mammary bone metastasis in rats with anti il 6r tocilizumab antibodies

    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


    Activation of notch pathway and osteosarcomas

    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


    Role of adiponectin in myelomas

    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


    Role of metalloproteinase mmp 7 in myeloma

    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


    Degenerative disc disease blame the hedgehog

    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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