The molecular mechanism of inflammatory bone resorption

1s

Abstracts

Bone Vol. 27. No. 4, Supplement October 2000: I s-54s

17

18 OSTEOGENESIS

JMPERFECTA 2000

D. Sillence Department of Paediatrics & Child Health, University of -I Sydney 2000. The Osteogenesis Imperfecta syndromes are characterised by bone fragility throughout life. Osteoporosis results in the majority of these disorder although young children with 01 may have bone fragility without evident osteoporosis. Although 13 “types” are distinguished in the international nomenclature based on combination of genetic, histomorphometric, biochemical and molecular findings, the pathogenesis of these “types” is not completely understood. Through the work of Glorieux and colleagues at the Shriner’s Hospital, Montreal, it is now apparent that while most types of 01 have decreased bone matrix production at the cellular level, there is an increased recruitment of osteoclast to the skeleton reflected in However markers of increased increased markers of bone produdion. bone turnover reflecting osteoclast resorption are also elevated and the osteopenia of the Osteogenesis Imperfecta syndromes commonly results from a cumulative annual negative increment in bone density or an increment which while positive lags behind normal increments with growth. Adults with Osteogenesis Imperfecta continue to have increased bone turnover throughout life. Therapies such as growth hormone increase both bone production and bone turnover. The bisphosphonates represent the major break through in 25 years of Osteogenesis Imperfecta research as they slow bone resorption without impairing bone formation.

I10

19 THE MOLECULAR BONE RESORPTION T Suds’,

M Inada2,

‘Department Tokyo,

C Miya&,

Shawa Tokyo

known

of bone

osteocla
differentiation

(ODF)/receptor indicating

that

University University

by

bone

help

and

School

N Takahashi’.

of Dentistry,

of Pharmacy

a

and

and Life Science,

strongly

Inhibited

by

TNF

TNFR2),

hut

factor

(OCIF).

TNFa

occurs

not

by

indicating by

failed

indicates

that LPS

pathway<:

one

induces

macrophages,

EP4

induce

the

which

are

t& induce

production in turn

without

by TNFu 2 (TNFRl

was and

inhibitory

into osteoclasts

by

ODF/RANKLRANK

differentiation

involved osteoclast

of

M-BMM+

into

in the

through

directly

acts

TNFRt and TNFRZ to induce osteoclast osteoblastr did not appear to be involved.

LPS-induced

bone

formation

by two

different

pathway

involving

TNFa.

is an ODFiRANK-independent

TNFn

1 and

of M-BMM$ of

M-CSF-

osteoclasts

formation type

formation. of

that lipopolysaccharides (LPS)-induced bone mice of EP4, a subtype of PGEl receptor.

sienals

appeared

osteoclast into

factor

(0PG)iosteoclastogenesis

independent

to

osteoclasts. More recently, we found 1015 did not occw in knockout resorption.

receptor

in the induced

mechanism,

differentiation

Osteoclast

that differentiation

a mechanism

IL-l

interaction.

for IL-l-induced

osteoprotegerin

role IL-1

differentiation

(M-BMM+)

cells.

a major

(RANKL).dependent

stimulated

of osteoblasts/stromal against

play

inflammation.

osteoclast

&and

IIIPITOW macrophages

antibodies

by

classical

are essential

TNFa

TNFa

induced

of NFkB

that osteoblasts mouse

IL-1

resorption

activator

contrast,

dependent

I.PS

N Udagawa’,

JAPAN It is well

This

OF INFLAMMATORY

K Kobayashi’,

of Biochemistry,

pathogen&s

any

MECHANISM

of Biochemistry,

‘Department

In

IN VITRO AND IN VIVO MODEL SYSTEMS USED 1‘0 ASSESS BONE-ACTIVE FACTORS .I Cornish. Department of Medicine. University of Auckland. Auckland, New Zealand Bone is a dynamic. complex, living tissue that is continually being remodelled due to the coupled actions of osteoclasts resorbing old bone and osteoblasts laying down new bone. Osteotropic hormones and local factors control the dcvelopmcnt and function of bone cells. Although numerous bone-active factors have been defined, there arc likely to be many more that still remain unidentified. With the development of various assays in osteoblast and osteoclast biology we now have some excellent tools available for screening such potential factors in a controlled environment. This session is designed to provide an over\,iew of successful approaches for identifying novel bone-active factors using in vitro and in viva models. The review will he illustrative rather than comprehensive and will discuss technical aspects of variousmethodologies including: osteoblast cell cultures hone marrow cultures isolated mature osteoclast cultures bone organ cultures local injectIon in viva models systemic models. In outlining these assays, their advantages. limitations and applications will he discussed. The USCof primary cultures compared to cell-lines will also be considered. Ultimately. the choice of method depends on the objective of individual studies.

toll-like

receptor

on osteoclast

4

progenitors

(TLRI)

in

through

differentiation. In this pathway, The other pathway is the classical

ODF/RANKLdependent pathway. In the classical pathway, LPS induces PGE2 production through TLR4 in osteoblasts and macrophages, which in turn ~nduccs ODFIRANKL throueh EP4 in asteoblasts. ODF then binds ODF rcccptor (RANK) in osteoclast progenitors by cell-cell contact, which D

\t~mulates

osteoclast

WC conclude also pathologlcal

differentiation. that osteoblasts

bone resorption

are involved via ODF/RANKL

in not only physiological,

but

MICROARCHITECTURAL ASSESSMENT OF BONE HK Genant,Osteoporosis & Arthritis Research Group, University of California San Francisco Noninvasive and/or nondestructive techniques can provide structural information about bone, beyond simple bone densitometry. While the latter provides important information about osteoporotic fracture risk, many studies indicate that BMD only partly explains bone strength. Quantitative assessment of macrostructural characteristics such as geometry, and microstructural features such as relative trabecular volume, trabecular spacing, and connectivity may improve our ability to estimate bone strength. Methods for quantitatively assessing macrostructure include (besides conventional radiographs) computed tomography, particularly volumetric quantitative computed tomography (vQCT). Methods for assessing microstructure of trabecular bone noninvasively and/or nondestructively include high resolution computed tomography @CT), micro computed tomography @CT), high resolution magnetic resonance (hrMR), and micro magnetic resonance pMR. Volumetric QCT, hrCT and brMR are generally applicable in viva; pCT and pMR are principally applicable in vitro. Despite progress, problems remain. The balance between spatial resolution and sampling size, or between signal-to-noise and radiation dose or acquisition time, needs further consideration, as do complexity and expense vs availability and accessibility. Clinically, challenges for bone imaging include balancing the advantages of simple hone densitometry vs the more complex architectural features of bone, or the deeper research requirements vs broader clinical needs. Biological differences between the peripheral appendlcular skeleton and the central axial skeleton must be further addressed. Finally, the relative merits of these sophisticated imaging techniques must he weighed with respect to their applications as diagnostic procedures requiring high accuracy or reliability versus their monitoring applications requiring high precision or reproducibility.