doi:10.1006/cyto.2000.0747, available online at http://www.idealibrary.com on
REVIEW ARTICLE
gp130 CYTOKINE FAMILY AND BONE CELLS
Dominique Heymann1,2* and Anne-Valérie Rousselle1
Bone tissue is continually being remodelled according to physiological circumstances. Two main
cell populations (osteoblasts and osteoclasts) are involved in this process, and cellular activities
(including cell differentiation) are modulated by hormones, cytokines and growth factors. Within
the last 20 years, many factors involved in bone tissue metabolism have been found to be closely
related to the inflammatory process. More recently, a cytokine family sharing a common signal
transducer (gp130) had been identified, which appears to be a key factor in bone remodelling.
This family includes interleukin 6, interleukin 11, oncostatin M, leukaemia inhibitory factor,
ciliary neurotrophic factor and cardiotrophin-1. This paper provides an exhaustive review of
recent knowledge on the involvement of gp130 cytokine family in bone cell (osteoblast,
osteoclast, etc.) differentiation/activation and in osteoarticular pathologies.
2000 Academic Press
Bone is a specialized connective tissue that,
together with cartilage, makes up the skeleton system.
Bone tissue has various functions, including mechanical properties (offering the site and support for
muscle tissue insertion for locomotion), protective
properties for vital organs (lung, heart, brain, bone
marrow, etc) and a metabolic role (bone is the main
reserve of ions for the organism, especially calcium and
phosphate). Bone tissue results from the activities of
many cell lineages, including mainly osteoblasts, osteocytes and osteoclasts. Osteoclasts are multinucleated
cells that possess several characteristic features, such as
a highly polarized morphology, apical differentiation
adjoining the calcified matrix in resorption (known as
the ‘‘ruffled border’’), and numerous mitochondria
(Fig. 1A). Osteoblasts are bone-forming cells (Fig. 1B)
which are progressively transformed into osteocytes (Fig. 1C, D) imprisoned in their own secretion
products which form lacunae after mineralization.
From the 1Laboratoire de Physiopathologie de la Résorption
Osseuse, EE 99-01, Faculté de Médecine, 1 rue Gaston Veil,
44035 Nantes cedex 1, France; 2Laboratoire d’Histologie et
Embryologie, Faculté de Médicine, Nantes cedex 01, France
*Correspondence
to:
Dominique
Heymann.
E-mail:
[email protected]
Received 22 March 2000; accepted for publication 22 March 2000
2000 Academic Press
1043–4666/00/101455+14 $35.00/0
KEY WORDS: gp130/IL-6/IL-11/leukaemia inhibitory factor/ciliary
neurotrophic factor/oncostatin M/ cardiotrophin-1/bone/
osteoblast/osteoclast
Abbreviations used: CNTF: ciliary neurotrophic factor;
CT-1: cardiotrophin-1; gp: glycoprotein; IL: interleukin; LIF:
leukaemia inhibitory factor; OSM: oncostatin M
CYTOKINE, Vol. 12, No. 10 (October), 2000: pp 1455–1468
These cells, which have an extensive endoplasmic
reticulum and numerous free ribosomes in the cytoplasm, are connected by gap junctions. Secondary cell
types such as monocytes/macrophages and endothelial
cells also contribute to the bone remodelling by direct
contact with osteogenic cells or by the release of
soluble factors (cytokines, growth factors). In 1969,
Frost showed that osteoblasts and osteoclasts are
closely associated in time and space.1 Thus, after
receiving a bone stimulus (i.e. mechanical load,
hormones, growth factors) from the lining, osteoblastic
and osteoclastic cells appear on the bone surface and
resorb the mineral components of bone by an acid
extracellular mechanism.2–4 Osteoblastic cells stimulated by osteoclastic contacts and/or osteoclastic
soluble factors deposit osteoid on the resorption
site, initiating bone formation.5 Osteoblasts not only
initiate but also control bone mineralization.
Although all osteogenic cells (osteoblasts, osteoclasts) contribute individually to bone remodelling,
their cellular interactions control cellular activities and
the intensity of bone remodelling. These interactions
can be established through cell–cell contact, 6 which
may involved molecules from the integrin family 7 or
the release of many polypeptidic factors and/or their
soluble receptor chains.8–10 These factors can act
directly on osteogenic cells on their precursors and
control differentiation, formation and functions
(matrix formation, mineralization, resorption, etc.).
Among the known soluble polypeptide factors, a
pleiotropic cytokine family sharing a common signal
1455
1456 / Heymann and Rousselle
Figure 1.
CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468)
Ultrastructural morphology of the three main cell types of bone tissue.
(A) Human osteoclasts obtained from a patient with giant-cell tumour and cultured on dentine slices. Arrowhead: dentine; arrow: resorption
lacunae; asterisk: ruffled border; original magnification5000; bar: 4 m. (B) Murine osteoblast on the mineralization front; arrowhead: mineral
phases of bone surface; arrow: extensive mineralization on collagen fibres; original magnification7300; bar: 1 m. (C) Murine osteoblast
progressively imprisoned in the mineral phase (arrowhead). Arrow: canaliculi containing cytoplasmic processes; original magnification5000;
bar: 1 m. (D) Murine osteocytes enclosed in lacunae (arrowhead) formed in dense mineralized areas (arrow); *: mineral phases of bone; original
magnification5000; bar: 1 m.
transducer (gp130)11 plays a key role during bone
remodelling. This family includes cardiotrophin-1,
CNTF, IL-6, IL-11, LIF and OSM, which all show
structural similarities (amino acid sequence, threedimensional structure) and produce similar activities
on a variety of target cells, including haematopoietic
cells, hepatocytes, neurons, embryonic stem cells and
bone cells.12–20
This review will focus on the involvement of gp130
cytokine family (cardiotrophin-1, CNTF, IL-6, IL-11,
LIF, OSM) on the formation and functions of osteogenic cells (osteoblasts, osteoclasts). An overview will
be provided of the potential implication of these
cytokines during osteoarticular pathologies.
Leukaemia inhibitory factor (LIF), oncostatin M
(OSM) and bone cells
LIF and OSM are clearly related cytokines whose
genes are located on chromosome 22q12 distal to the
Ewing’s sarcoma break-point and within 500 kb of
each other.21 Moreover, OSM can mimic LIF activities
both in vitro and in vivo and shares common gp130
and gp190 transducing receptor subunits with LIF,
accounting in part for their redundancy.21–25 LIF is
produced by numerous cell types, including lymphocytes,26 monocytes,27 bone-marrow stromal28–30
and osteoblastic cells.31,32 Malignant cells also express
LIF cytokine.33,34 LIF produced by osteogenic cells
and mesenchymal cells is regulated by key molecules
gp130 cytokine family and bone cells / 1457
involved in bone metabolism, such as PTH and
PTHrP.31 Moreover, Pollock et al. have shown that
both LIF and IL-6 are physiologically important
mediators of at least some actions of PTH and
PTHrP.31,35 OSM production is generally restricted to
haemopoietic cells, and no production by osteogenic
cells has yet been detected.36–38
The first evidence of LIF activities during bone
remodelling steps was provided by Metcalf and
Gearing, who showed that mice engrafted with LIFcDNA transfected cells producing high amounts of LIF
developed a fatal syndrome within 12–70 days characterized by cachexia, excessive new bone formation and
ectopic calcifications in skeletal muscles and heart.39,40
The effect of LIF and OSM on bone remodelling may
be mediated by osteoblasts and bone-marrow stromal
cells which, unlike osteoclasts, express receptors for
both.24,41–43 However, the activity of LIF and the presence of LIF receptor chain (gp190) have recently demonstrated in osteoclast-like cells cultured from human
giant-cell tumour of bone.44,45 Nonetheless, LIF and
OSM stimulated osteoclast-like cell formation and
resulting resorption mechanisms when bone-marrow
cells were co-cultured in vitro in the presence of
osteoblasts.46 Their receptors are active on osteoblastic
cells and transduce the signal via protein phosphorylations (tyrosine kinase47–51 and non-tyrosine kinase52
pathways). At the present time, osteoblasts appear to
be the main target of LIF and OSM and could act
indirectly on osteoclasts via the release of prostaglandins.53–55 IL6-type cytokines (LIF, OSM, IL-6)
that utilize the gp130 signal transducer are potent
anti-apoptotic agents on osteoblastic cell types
(MC3T3-E1 and MG-63).56 Thus, these cytokines like
TGF- are able to counteract the effect of serum
starvation or TNF. The induction of apoptosis in
human MG-63 cells is associated with an increase in
the ratio of the pro-apoptotic protein bax to the
anti-apoptotic protein bcl-2, whereas oncostatin M
prevents this change. LIF and OSM also influence the
differentiation/proliferation system of osteoblasts. The
effects of LIF on the proliferation of osteoblastic cells
are reported to have a stimulatory or inhibitory effect
(depending on the model used, on the age of the
animals and the site).57–63 If LIF and OSM can
modulate the differentiation/proliferation system, they
can also influence the physicochemical characteristics
of the bone mineral formed (i.e. ionic microenvironment, etc.). Such variations have been observed in a
murine heterotopic calcification model,64 where LIF
and OSM increased the number of bone-marrow
stromal cell progenitors with osteogenic potential.65
In this model, both cytokines induced an immature
state of the mineral deposited on the extracellular
matrix, as revealed by the presence of environment
rich in labile non-apatitic phosphate, carbonate and
HPO4.66 Similar results have been obtained in in vitro
rat bone-marrow stromal cell cultures.67
The effect of LIF and OSM on osteoclastic
activation and resorption are not so clear. Thus,
Turner et al. analysed the effects of injected LIF in
growing rats and have observed that high systemic
concentrations of LIF resulted in hypercalcaemia
with no changes in bone turnover.68 LIF and OSM
increased the amounts of mineral deposited in these
various models, but also modified the quality of the
mineral, which is one of the key parameters regulating
the resorption mechanism induced by osteoclasts.69
Although both cytokines can influence mineral phases
and osteoclast activities, no direct action on these cells
has yet been demonstrated, essentially because of the
difficulties in obtaining a pure population of osteoclasts. However, numerous data have reinforced the
potential role of both cytokines in resorption
mechanisms.43–46,70–72 For example, in vitro exposure
of human long-term bone-marrow culture to recombinant human LIF and OSM significantly increased
the number of multinucleated cells formed after three
weeks of culture.73,74 The multinucleated cells formed
expressed the macrophage polykaryon phenotype and
were capable of low-grade resorption in the presence of
bone-marrow stromal cells. OSM reduced the resorption induced by these cells. OSM and LIF could thus
modulate bone remodelling toward such mechanisms
(orientation of bone-marrow mononuclear cell differentiation to macrophage polykaryon phenotype).
These results are in agreement with those obtained by
Sarma and Flanagan, who showed that LIF did not
increase bone resorption but upmodulated 23c6positive cells (an antibody that recognizes the vitronectin receptor, which is one of the characteristics of
osteoclasts) in a human bone-marrow mononuclear
cell fraction co-cultured with human bone-marrow
stromal cells.75 Moreover, Benahmed et al. found that
LIF inhibits the differentiation of monocytes into
macrophages and their ability to manifest macrophagic
activity.76 Similarly, Sabokbar et al. have shown that
LIF, like IL-4, inhibits the osteoclastic differentiation (tartrate-resistant acid phosphatase activity and
lacunar bone resorption) from monocyte co-cultured
with osteoblast-like cells in presence of polymethylmethacrylate wear particules.77
Numerous proteinases produced by bone cells
(osteoblasts, osteoclasts) contribute to bone remodelling. Thus, the prevention of bone resorption by collagenase and/or gelatinase inhibitors or by cysteine
inactivators has provided direct evidence for the participation of cysteine proteinases and matrix metalloproteinases in bone resorption. Varghese et al.78,79
have demonstrated that LIF and OSM stimulates
collagenase-3 (MMP-13) and tissue inhibitors of
metalloproteinase-1 (TIMPs) expression in osteoblasts,
1458 / Heymann and Rousselle
but do not regulate the expression of gelatinase A
(MMP-2), B (MMP-9), TIMP-2 and TIMP-3 in
primary cultures of osteoblast-enriched cells isolated
from fetal rat calvaria.80 These results are in agreement
with those obtained by Damiens et al. (personal communication) in osteoblastic type cells such as SaOS2
or MG-63,81 and those of Cowell et al. who showed
that OSM upmodulated collagenase-3 expression in
chondrosarcoma cells.82
Various transgenic or knockout mice have been
developed to determine the real involvement of LIF
and OSM in bone remodelling.83–88 Bone metabolic
evidence is suggested by data obtained from chronic
overproduction of LIF following the introduction of
LIF transgenes.39,40 Shen et al. generated a transgenic
mouse line that expressed diffusible LIF protein in T
cells.83 No abnormalities in bone growth appear to
have been detected in this study. However, the limited
overproduction of LIF protein by T cells made the
evaluation of LIF effects difficult. Escary et al.84 as well
as Stewart et al.85 have developed LIF-deficient mice
derived by gene-targeting techniques. Their model indicates that transient expression of LIF in mice is essential for blastocyte implantation and maintenance of
haematopoietic stem cells and thymocyte stimulation.
They also observed that viable homozygous mice
deficient in LIF expression had a retarded postnatal
growth rate (body weight 25–35% smaller). However,
no specific analysis of bone tissue was performed in
their studies. In transgenic mice overexpressing OSM,
Malik et al. observed that the animals developed
osteopetrotic bone tissue, possibly by stimulation of
bone formation and inhibition of bone resorption.84 As
the effects of both cytokines can be redundant with
those of IL-6, IL-11, CT-1 and CNTF, gp130 gene
knockout mice and gp190 gene knockout mice have
been generated.87,88 Kawasaki et al. compared bone
tissue from gp130-deficient and wild-type newborn
mice87 and observed a decrease in trabeculae at the
metaphysical region in tibia and radii of deficient mice
as well as an increase in the number of osteoclasts. No
apparent differences were noted in the distribution of
alkaline-positive osteoblasts and the osteoid surface on
trabecular bone of the metaphysical region, whereas
the volume of mineralized trabecular bones was
decreased at mandibulae. These data confirm the role
of gp130 cytokine family during bone remodelling, but
also indicate that osteoclast formation is not solely
dependent on gp130 signalling. These cytokines could
have an inhibitory effect on osteoclastic formation,
and the persistence of osteoclasts in gp130-deficient
mice may be caused by the functional redundancy of
bone-resorbing factors. Similarly, experiments performed with gp190-deficient mice88 showed that this
defect induced a reduction of fetal bone volume. The
decrease of osteoid volume associated with an increase
CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468)
of osteoclast number resulted in osteopenia of perinatal bone. These results confirm those obtained in
gp130-deficient mice.
INTERLEUKIN 6 (IL-6), INTERLEUKIN 11
(IL-11) AND BONE CELL
IL-6 and IL-11, like LIF, OSM, CT-1, and CNTF,
are multifunctional cytokines16–19,89 which share the
common receptor transducer gp130.11,20,48,90 A large
number of cell types express IL-6 such as monocytes,
fibroblasts, endothelial cells, chondrocytes, bonemarrow stromal cells, keratinocytes and bone cells.91
These large production sites correspond to numerous
biological activities, such as functions in immune cells,
haematopoiesis, acute phase response during inflammation, the neurological system and bone remodelling
(see references92,93). The main source of IL-6 in bone is
osteoblastic cells and stromal cells, and not osteoclastic
type cells.94 IL-6 is produced by osteoblastic-type cells
and bone-marrow stromal cells and is modulated by
various agents (Tri-iodothyronine, IL-13, sphingosine,
retinoic acid, prostaglandins, oestradiol, basic FGF,
TNF, etc.)93,95–103 and in specific conditions such as
gravity.104 IL-11 was originally discovered as a crossreacting cytokine in an IL-6 bioassay.105 IL-11 gene is
expressed in a variety of normal and cancer cells of
mesenchymal origin (bone-marrow stromal cells, lung,
uterus, connective tissues, skin, testis, etc.) and is
modulated by several inflammatory cytokines and
agonists as well as hormones.90 Primary human osteoblasts produce a very low amount of IL-11, which
is strongly upmodulated by TGF-1.106–108 IL-11 is
also produced by bone-marrow stromal cells and
modulated by osteotropic agents. Thus, its production
is stimulated by IL-1, PTH, basic FGF, and inhibited
by interferon-.109–112 IL-11 act synergistically with
other cytokines (IL-3, IL-4, IL-13, stem cell factor,
etc.) to stimulate various haemopoietic stages and
lineages. Thus, IL-11 stimulates the proliferation of
primitive stem cells. The other main activities concern
its effects on epithelial cells (inhibition of proliferation), neurogenesis (stimulation of the proliferation of
hippocampal neuronal cells), inflammation (stimulation of acute phase reactants; see reference90). These
results indicate that appropriate osteoblastic cells and
bone-marrow stromal cells are potent producers of
IL-6 and IL-11, which may be important components of the cytokine network mediating bone cell
communications during bone remodelling.
Although osteoblastic cells express IL-6 mRNA
and produce the protein, they apparently do not
respond to this factor.113,114 Few data have concerned
the effects of IL-6 on osteoblastic cells. ‘‘High’’ concentrations of IL-6 (>10 ng/ml) were found to produce a slight increase in tritiated thymidine in the
gp130 cytokine family and bone cells / 1459
UMR-106-01 tumour cell line.115 Like LIF and OSM,
IL-6 is a potent anti-apoptotic agent on osteoblastic
cells via transcriptional activation of the p21 gene.56,116
Moreover, IL-6-type cytokines stimulate mesenchymal
progenitor differentiation toward the osteoblastic lineage.117 However, Hughes et al. have shown that IL-6
inhibits bone formation118 in vitro, which suggests that
studies on the quality of the mineral phases formed in
presence of IL-6 could be crucial in determining the
real impact of this cytokine on bone formation. The
main activity of IL-6 on bone is its effect
on osteoclastogenesis and bone resorption. Thus,
Kuhihara et al. showed that IL-6 stimulates osteoclastlike formation in long-term human marrow culture by
IL-1 release, whereas the addition of anti-IL-1 inhibits
the increase in osteoclast formation induced by IL-6.119
IL-6 also mediates the same stimulatory effects as
TNF120 and PTH.121 These data, which have been
confirmed in vivo122 and depend on the model used.123
IL-6 also enhances PTHrp-mediated hypercalcaemia
and bone resorption, by increasing the pool of osteoclastic progenitors and then after differentiation of
mature osteoclasts.124
In a murine model, IL-6 strongly increases the
formation of multinucleated cells only in the presence
of IL-6 soluble receptor gp130.47 Flanagan et al.
demonstrated, using a model of human bone-marrow
stromal cells recharged with non-adherent bonemarrow cells, that IL-6 failed to induce a similar
stimulatory effect.125 In this study, IL-6 was not able to
replace the stromal factor(s) required for the formation
of cells capable of resorbing bone. These authors
concluded that IL-6 is not critical in stimulating osteoclastic bone resorption. IL-6 and LIF similarly had no
effect in a murine model.126 This discrepancy can be
explained by the fact that the exact nature of these
cells, referred to by some authors as ‘‘osteoclast-like’’,
remains controversial (osteoclasts or macrophagepolykaryons?).10 Curiously, IL-6 produced by osteoblasts in response to CD34 + haematopoietic
bone-marrow cells127 which are able to differentiate in
osteoclasts under specific conditions.128 In this case,
what is the real involvement of IL-6 in the dichotomic
system: osteoclast and haematopoietic differentiation?
The effect of IL-6 on osteoclasts in human bone
marrow has been analysed recently by stromal cells
transfected by a cDNA coding for human IL-6 and
injected into human bone implants implanted in NOD/
SCID mice.129 These data demonstrate that only
implants engrafted with IL-6/stromal cells had an
upmodulation in osteoclast-lined mineralized trabecular bone surface. Similarly, in the human giant-cell
tumour model, IL-6 antisense deoxyoligonucleotides
inhibit bone resorption by these osteoclast-like cells.130
IL-6 produced by these tumours may then be involved
in the autocrine induction of osteolysis, which is associ-
ated with biologic aggressiveness.131 IL-6 exerts its
activities via a cell-surface receptor which consists of
two glycoproteins, gp80 and gp130. When gp80 is
occupied by IL-6, this complex binds to gp130 and
transduces IL-6 signals. In this context, various studies
have analysed the expression of these receptors to
determine the target cells of IL-6 during osteoclastic
differentiation/activation.132,133 Thus, Udagawa et al.
have demonstrated that induction of osteoclast differentiation by IL-6 is dependent on IL-6 receptors
expressed on osteoblastic cells but not on osteoclast
progenitors.132 Tamura et al. showed that neither
recombinant IL-6 nor soluble IL-6 receptor (gp80)
induced osteoclast-like formation from mouse bonemarrow cells. Conversely, addition of IL-6 and IL-6soluble receptor induced osteoclast-like formation.46
However, these apparently contradictory results were
mainly due to the differentiation level of bone tissue
used and to methodological differences. More recently,
Gao et al. showed that gp130 and IL-6 receptors are
expressed on tartrate-resistant acid phosphatasepositive mononuclear cells and isolated murine osteoclasts. In this model, IL-6 caused enhancement of the
resorbing activity in a dose-dependent manner, indicating the involvement of IL-6 in the formation and
activation of osteoclasts.132 The presence of IL-6 receptors on osteoclast membrane has been confirmed by
confocal microscopy and by in situ reverse transcriptase PCR histochemistry.133 Adebanjo et al. also
found that IL-6, but not IL-11, reverses the inhibition
of osteoclastic bone resorption induced by high extracellular Ca2+ and may sustain osteoclastic activity
versus an inhibitory Ca2+ level generated locally during resorption.134 The importance of the IL-6 function
during bone remodelling has been confirmed in
oestrogen-deficient animals.135,136 These studies indicate that ovariectomy does not induce any change in
either bone mass or bone remodelling rates in the
IL-6-deficient mice and that anti-IL-6 monoclonal
antibodies inhibit upmodulation in osteoclast precursors occurring in oestrogen depleted mice. These
results are in accordance with those obtained by
Girasole et al. who demonstrated that ovariectomized
animals display elevated serum levels of IL-6 that can
be normalized by administration of oestradiol.99 However, though serum IL-6 levels increase with age, no
correlation was found between bone turnover, ovarian
function and serum IL-6 level in a study of 80 normal
women (24–87 years of age).137 These results are not
concordant with the study of Bismar et al.138 who
found increased IL-6 levels in patients with postmenopausal osteoporosis. At the present time, the actual
involvement of IL-6 in patients with postmenopausal
osteoporosis is still unclear. Moreover, macaques
injected with recombinant IL-6 showed no upmodulation of calcium release, thereby indicating that there
1460 / Heymann and Rousselle
is no modulation of bone resorption in vivo.139 Thus,
there is still controversy about the candidate molecules
that stimulate bone resorption during oestrogen depletion and subsequent osteoporosis. The protective
effects of oestrogen for bone could involve two other
candidates, namely TNF140 and/or IL-11.141 To complicate the various observations, Schiller et al. have
observed that osteoclastogenesis induced by 1, 25
(OH)2D3 is partially dependent on IL-6 and is modulated by 17-oestradiol through interference IL-6
receptor activation as well as inhibition of IL-6 produced by bone-marrow stromal cells.100 IL-6 could
also be an appropriate candidate during bone loss
caused by androgen deficiency,142 insofar as 17oestradiol and dihydroxytestosterone decrease the
expression of gp130 and gp80 in the murine bonemarrow cells.143 These studies have been supplemented
by those of Nishida et al., who used a monoclonal
antibody in normal and ovariectomized rats.144
Osteoclast-like cells, as well as osteoblasts, express
IL-11 receptor transcripts and a sequential relationship
exists between expression of the calcitonin receptor
mRNA and IL-11 receptor mRNA.145 Gp130 signals,
evoked by IL-11, are indispensable for IL-1-induced
osteoclast formation. Further studies are required to
elucidate the role of IL-11 in mature osteoclasts functional IL-11 receptors on osteoclasts (IL-11 does not
influence by itself osteoclast survival and anti-gp130
antibody does not influence pit resorption by these
cells).145 However, IL-11 upmodulated the formation
of osteoclast-like cells from mouse bone-marrow
cells,108,145–147 as well as the surface of calcified matrix
resorbed by these cells which involves both metalloproteinases and products of achidonic acid metabolism.145,147 IL-11 has been implicated in oestrogen
deficiency-induced bone loss. Thus, a neutralizing
monoclonal antibody inhibited the osteoclastogenesis
induced by 1, 25 (OH)2D3 and PTH in both normal
and ovariectomized mice (IL-6 antibody was an inhibitor only in ovariectomized mice).108 Recent in vitro
data also indicate that IL-11 production induced by
PTH or IL-1 in human bone-marrow stromal cells was
not modulated by 17-oestradiol109 and that injected
recombinant IL-11 did not modify biochemical parameters of bone remodelling in adult ovariectomized
rats.148 Moreover, IL-6 and IL-11, like LIF and OSM,
can induce bone resorption by modulating proteinase
release by bone cells.81,147,149
Transgenic or knockout mice have been developed
to determine the real involvement of IL-6 in bone
remodelling (Table 1). Thus downmodulation in
osteoblasts and in osteoid, as well as a decrease in
osteoclasts and bone resorption, has been observed
predominantly in transgenic mice overexpressing IL-6.
These modulations resulted in the suppression of
bone turnover.150 Overexpression of IL-6 also induced
CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468)
plasmocytomas, indicating the potential involvement
of this cytokine in myeloma pathology.151,152 The role
of IL-6 during bone turnover was confirmed in IL-6deficient mice which showed an increase of bone turnover and were protected from bone loss caused by
oestrogen depletion.136 Similar transgenic mice have
been generated with IL-11, but no data are available
concerning the quality of mouse bone, and bone
turnover has not been studied.153,154
CARDIOTROPHIN-1 (CT-1) AND CILIARY
NEUROTROPHIC FACTOR (CNTF) AND
BONE CELLS
Although considerable data have been published
concerning the role of CT-1 and CNTF, particularly in
muscular and nervous systems,13,14 no specific study
has been performed concerning the effects of these
cytokines on the bone system. Apparently, CNTF did
not modify embryonic development and growth in
CNTF gene knockout mice.14
gp130 CYTOKINE FAMILY AND
OSTEOARTICULAR PATHOLOGIES
The gp130 cytokine family is involved in osteoarticular pathologies, mainly in osteolytic diseases
(giant-cell tumours, Paget’s disease, bone metastasis)
and in rheumatoid arthritis. Thus, because of its
involvement in bone remodelling and its expression by
some tumours cells, LIF has been studied in vivo in
human primary benign and malignant tumours.155 In
this study, LIF was never detected in any sera tested,
in control urine samples, or in supernatants from
normal cancellous bone cultures. A high level of LIF
was found in all supernatants from malignant tumour
cultures (100%) and in supernatant from cultured
benign tumours (86%). LIF levels were particularly
high in supernatant from chondrosarcoma. Immunohistochemical analysis revealed that LIF is present in
all benign endochondromas and malignant chondrosarcomas, but not in control tissue.156 The cytokine is
localized in cartilage cells, and the number of stained
cells ranges from less than 5% in endochondroma of
the hand to more than 70% in high-grade chondrosarcoma. These studies raise the question of the significance of LIF in tumour-associated bone resorption
and the potential role of this cytokine as a prognostic
marker. The role of LIF during malignant osteolysis
has been confirmed by Gouin et al., who found the
presence of LIF receptors on osteoclast-like cells from
human giant-cell tumours.44 Similarly, IL-6 could be
involved during osteolysis induced by giant-cell
tumours, as described by Reddy et al.130,157 Interleukin
6 antisense deoxyoligonucleotides inhibited bone
gp130 cytokine family and bone cells / 1461
TABLE 1.
Transgenic mice for the gp130 cytokine family and their receptor subunits: effects on bone tissue
Type of mice
Effects observed
Authors (references)
Transgenic mice overexpressing LIF in T lymphocytes
Normal growth
Shen et al.83
Trangenic mice overexpressing IL-6
Decrease in osteoblasts and osteoid, and decrease of both
osteoclast number and bone resorption
Plasmocytoma formation
Suppression of bone turnover
Kitamura et al.149
Suematsu et al.150,151
Trangenic mice overexpressing OSM
Osteopetrotic bone (stimulation of bone formation and
inhibition of bone resorption)
Malik et al.84
LIF gene knockout mice
Retarded postnatal growth rate
Escary et al.85
Stewart et al.86
IL-6 gene knockout mice
No significant change in osteoclast and osteoblast surfaces
Increase of bone turnover
Poli et al.135
CNTF gene knockout mice
Normal embryonic development and growth
Sariola et al.14
gp130 gene knockout mice
Osteopenia (decrease in the amount of trabeculae at the
metaphysical region in the tibia and radii)
Increase of osteoclast number
Kawasaki et al.87
gp190 gene knockout mice
Reduction of fetal bone volume (severe osteopenia of
perinatal bone)
Decrease in osteoid volume
Increase of osteoclast number
Ware et al.88
Targeted expression of IL-11 in mice
Not studied
Tang et al.152
Mice with targeted mutation of the IL-11 receptor
Not studied
Nandurkan et al.153
resorption by giant cells from human giant-cell
tumours of bone, demonstrating the autocrine biological activity of IL-6 on osteoclasts. Several models
inducing experimental bone metastasis158 have been
used to study the role of the gp130 cytokine family in
the development of bone metastasis. Bone-marrow
metastasis is usually the initial step in the formation of
bone metastasis, and interaction between tumour cells
and bone-marrow cells affects osteoclast formation in
bone marrow. Thus IL-6, IL-11 and LIF have been
suspected to participate in the formation of osteolytic
bone metastasis.159–164 This is the case of A375
melanoma cell line, which formed multiple osteolytic
lesions when cells were injected into the left ventricle of
mice.165 IL-6 and LIF produced by A375 cell lines may
be involved in the differentiation and activation of
osteoclasts in association with stromal cells during the
development of bone metastasis.166 IL-6 has been
reported to be involved in bone destruction in
malignant-hypercalcaemia.159–161 Similarly IL-11 produced by endothelial cells and cancer cells may induce
the formation of osteolytic bone metastasis.162,163
Akatsu et al. also found that the mouse mammary
tumour cell line, MMT060562, released LIF, which in
turn stimulated osteoclast formation via a stromal
cell-dependent pathway.164
IL-6 has been shown to play a key role in the
generation of plasmocytomas151,152, which has been
confirmed by Bataille et al.167,168 and more recently by
Nishimoto et al.169 and Zhang et al.170 whereas IL-6,
like IL-11, LIF and OSM, induces proliferation in
vitro of human plasmocytoma cells via their common
signal transducer, gp130. IL-6 is then expressed by
myeloma cells and mediates the autocrine growth of
myeloma cells.171 Moreover, Garrett et al. have shown
that IL-6 produced by activated osteoclasts enhances
myeloma growth in vivo.172 The pathogenesis of bone
lesions in multiple myeloma involves bone cells and
bone-marrow stromal cells,173,174 as well as various
molecules such as cytokines or proteinases.175 Raised
serum OSM was related to higher serum IL-6,
C-reactive protein levels and also 2microglobulin176,177 (which is considered to be the single most
important prognostic factor in multiple myeloma).178
Thus, OSM and IL-6 levels may be significant prognosis parameters. In Paget’s disease of bone, the main
abnormality concerns osteoclasts, which are increased
in size and possess a large number of nuclei.179 IL-6
and IL-6 receptors are strongly expressed by osteoclasts in patients with Paget’s disease and may be
involved in the differentiation/activation of osteoclasts
during this pathology.180
Rheumatoid arthritis is an autoimmune and systemic inflammatory disease of uncertain aetiology
characterized by acute phase proteins in serum, chronic
joint inflammation and severe cartilage alterations
(until complete destruction). Numerous cytokines have
been measured in the serum and/or synovial fluid of
1462 / Heymann and Rousselle
patients with rheumatoid arthritis, which is indicative
of their potential in this pathology. These factors
include IL-1 and TNF-,181,182 which are able to
induce cartilage proteoglycan catabolism in vitro and
in vivo,183–185 and the gp130 cytokine family (IL-6,
IL-11, OSM, LIF, CT-1, CNTF).186–191 The activity of
these cytokines on cartilage metabolism is varied. LIF
and OSM promote cartilage degradation in vitro192,193
and in vivo and have induced leukocyte infiltration in
goat joints.194,195 All members of the gp130 cytokine
family analysed (IL-6, IL-11, OSM, LIF, CNTF) suppressed proteoglycan synthesis in in vitro experiments.193 During rheumatoid arthritis, some potential
sources of the gp130 cytokine family are chondrocytes,
synoviocytes and leukocytes infiltrating joints (a
correlation has been found between LIF expression in
synovial fluid and leukocyte count186).191,196–200 The
destruction of cartilage in rheumatoid arthritis may be
also controlled by the release of proteases and their
inhibitors, which degrade various components of the
extracellular matrix. Thus, the gp130 cytokine family
can influence cartilage degradation by modulating
these protease activities.201–205 Despite the numerous
studies published on this subject, the role of the gp130
cytokine family in the regulation of cartilage macromolecule metabolism is still uncertain.206 Histologic
analysis has revealed peri-articular trabecular bone
resorption in patients with rheumatoid arthritis.207
Takayanagi et al. and Fujikawa et al. have described a
new mechanism of bone destruction in rheumatoid
arthritis in which synovial fibroblasts can support
in vitro differentiation of monocytes/macrophages in
osteoclasts.208,209 These locally produced factors could
contribute at least partially to joint destruction
through osteoclastogenesis.210,211
CONCLUDING COMMENTS
During the last decade, various soluble factors
have been found to act on bone cells. However, it is
difficult to establish a hierarchical order for these
factors. Members of the gp130 cytokine family appear
to play a key role in bone remodelling events by acting
on both osteoclasts and osteoblasts. The fact that these
factors are detected during osteoarticular pathologies
is indicative of their importance. Nevertheless, their
exact role (bone apposition, bone resorption) in bone
cells remains an open question. Although cytokines,
growth factors and hormones are the main protagonists of bone remodelling, phylogeny can provide
further clues to this phenomenon.212 Thus, it has been
shown that the osteoclast appeared during the evolutionary transition of bony fishes from salt to fresh
water where calcium homeostasis could no longer be
regulated by transport across epithelia in contact
with salt water. Therefore, bone represents a stock of
CYTOKINE, Vol. 12, No. 10 (October, 2000: 1455–1468)
calcium ions that regulate cellular activity, which in
turn influences calcium release from bone. Calcium
would thus appear to be one of the primary parameters
of bone remodelling, acting before cytokines, growth
factors and hormones.
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