British Journal of Orthodontics/Vol.

25/1998/101–107

Scientific Section

REVIEW SERIES
“This is the first in a series of articles where advances in basic sciences relevant to clinical orthodontics, are presented by
clinicians with a research interest. This first article on bone modelling by Peter Hill, sets a high standard for successive
articles. Further articles on muscle biology, regulation of tissue turnover, craniofacial development, cell signalling and
cytokines will appear in future journal issues. It is hoped that these articles will be of interest, not only to postgraduate
students but also established clinicians”.
J. Sandy, Sub Editor

Bone Remodelling
P . A . H I L L , B . D . S ., F . D . S ., M . O R T H ., B . S C , M . S C ., P H . D .
Department of Orthodontics and Paediatric Dentistry, UMDS of Guy’s and St.Thomas’ Hospitals, London Bridge, London SE1 9RT.

Introduction of clinical orthodontics and for its future development as an

academic discipline. This review outlines our current
The remarkable increase in research in bone biology understanding of bone remodelling and its regulation as a
during the last two decades has both enhanced our under- basis to addressing the unanswered questions.
standing of the regulation of bone remodelling and
enabled us to define some of the major unanswered
questions. Bone is a dynamic tissue that constantly under-
Bone Structure and Remodelling
goes remodelling even once growth and modelling of the
skeleton have been completed. Bone remodelling is a Bone is a specialized connective tissue composed of both
coupled process in which there is localized removal of old mineral and organic phases that is exquisitely designed for
bone (resorption) and replacement with newly formed its role as the load-bearing structure of the body. To
bone. The process is complex, requiring interaction accomplish this task, it is formed from a combination of
between different cell phenotypes, that are regulated by a dense compact bone and cancellous (trabecular) bone that
variety of biochemical and mechanical factors. It is likely is re-inforced at points of stress. The mineral phase of the
that the major reason for remodelling is to enable the skeleton contributes about two-thirds of its weight, the
bones to respond, and adapt to mechanical stresses as remaining one-third is organic matrix, consisting primarily
occurs as a result of physical exercise and during mech- of type I collagen and small amounts of non-collagenous
anical loading as occurs during orthodontic tooth proteins. Two principle cell types are found in bone, the
movement. Abnormalities in bone remodelling occur in osteoclast, and the osteoblast, which are the major effectors
some of the most common diseases that affect humans such in the turnover of bone matrix (Fig. 1). The osteoblast
as osteoporosis, periodontitis, arthritis, and tumour- produces the matrix which becomes mineralized in a well
induced osteolysis. Although these disorders are common regulated manner. This mineralized matrix can be removed
and cause considerable suffering, in most cases little is by the activity of the osteoclast when activated.
known of the mechanisms responsible for the dysfunc- Bone is constantly undergoing bone remodelling which
tional bone remodelling that characterizes them. This is is a complex process involving the resorption of bone on a
not unexpected, since at present we do not understand the particular surface, followed by a phase of bone formation.
mechanisms responsible for the control of normal bone In normal adults, there is a balance between the amount of
remodelling or how it is so highly co-ordinated and bone resorbed by osteoclasts and the amount of bone
balanced. However, novel techniques for studying bone formed by osteoblasts (Frost, 1964). Bone remodelling
function at the cellular level (bone cell and organ culture), occurs in small packets of cells called basic multicellular
the availability of recombinant molecules and comple- units (BMUs), which turn bone over in multiple bone
mentary DNA probes, the new understanding revealed by surfaces (Frost, 1991); at any one time, ;20% of the
gene ‘knockout’ and transgenic experiments, as well as cancellous bone surface is undergoing remodelling. Each
new techniques for studying bone function at the clinical BMU is geographically and chronologically separated from
level, should clarify the control mechanisms for the cellular other packets of remodelling. This suggests that activation
events in normal bone remodelling, and seem certain to of the sequence of cellular events responsible for
lead ultimately to new information and treatment remodelling is locally controlled, perhaps by autocrine
measures to inhibit or prevent these disorders. Further- or paracrine factors generated in the bone micro-
more, an understanding of the biochemical and molecular environment. The current concept of bone remodelling is
mechanisms that enable bone cells to adapt to changes in based on the hypothesis that osteoclastic precursors
their mechanical environment is essential for the practice become activated and differentiate into osteoclasts, and

0301-228X/98/002000+00$02.00 © 1998 British Orthodontic Society

102 P. A. Hill Scientific Section BJO Vol 25 No. 2

this begins the process of bone resorption. This step is

followed by a bone formation phase. The number of sites
entering the bone formation phase, called the activation
frequency, together with the individual rates of the two
processes, determines the rate of tissue turnover (Charles
et al., 1987; Ericksen et al., 1986).
The signal that initiates bone remodelling has not been
identified, but evidence shows that mechanical stress
can alter local bone architecture. The requirement for
mechanical tension in the formation of bony tubercles at
sites of tendon insertions is elegantly demonstrated in mice
in which both the myf-5 and myoD genes are inactivated
(Rudnicki et al., 1993). These mice lack bony tubercles
presumably as a result of impaired muscle development
and, therefore, reduced mechanical tension at tendon
insertion sites. While prostaglandins have been implicated,
how tension is sensed by resident bone cells and how such
FIG. 1 Light micrograph of trabecular bone. Multinucleate osteoclasts (large
arrows) are resorbing calcified bone in a Howship’s resorption lacuna, while
signals contribute to the cellular and molecular control of
osteoblasts (small arrows) are laying down matrix on the surface of osteoid. bone remodelling are major unresolved issues in skeletal
Osteocytes (arrowheads) are found within the mineralized matrix. biology. More recently, it has been shown that mechanical
(Haematoxylin and Eosin, x80, enlarged to 250% on reproduction). stress can be sensed by osteocytes and that these cells

FIG. 2. Stages of bone remodelling. Resorptive phase: activated multinucleated osteoclasts derived from bone marrow monocytes resorb a discrete area of
mineralized bone matrix. Reversal phase: subsequently osteoprogenitor (osteoblast precursor) cells, which can locally proliferate and differentiate into osteoblasts,
migrate into the resorption lacuna and disclose the former osteoclastic activity. Formative phase: the osteoblasts deposit new bone matrix, which is initially
unmineralized and called osteoid, and in this way fill the resorption lacuna. Resting phase: once embedded in osteoid, the osteoblasts mature into terminally
differentiated osteocytes. The osteoblasts lying on the surface of the newly formed bone packet are quiescent lining cells until activated.
BJO May 1998 Scientific Section Bone Remodelling 103

secrete paracrine factors such as insulin-like growth factor still unsettled. A model illustrating this ‘coupling’ process
(IGF)-I in response to mechanical forces (Lean et al., is presented in Fig. 3. During resorption, the osteoclasts
1996). Although IGF-I may act as a coupling factor in the release local factors from the bone, which have two effects:
bone remodelling cycle (see below), the signal that initiates inhibition of osteoclast function and stimulation of osteo-
the cycle remains elusive. The sequence of events in the blast activity. Moreover, osteoclasts themselves produce
normal remodelling cycle are always the same, osteoclastic and release factors that have a negative regulatory effect
bone resorption, a reversal phase, followed by osteoblastic on their activity, and enhance osteoblast function. Finally,
bone formation to repair the defect (Fig. 2). when the osteoclasts complete the resorptive cycle, they
The termination of bone resorption and the initiation of secrete proteins that later serve as a substrate for
bone formation in the resorption lacunae occurs through a osteoblast attachment (McKee et al., 1993).
coupling mechanism (Parfitt, 1982). The coupling process Bone remodelling is regulated by systemic hormones
ensures that an equivalent amount of bone is laid down and by local factors, which affect cells of both the osteo-
following the previous resorption phase. The detailed clast and osteoblast lineages and exert their effects on (i)
nature of the activation and coupling mechanism is still the replication of undifferentiated cells, (ii) the recruit-
unknown, although some growth factors and proteinases, ment of cells, and (iii) the differentiated function of cells
such as transforming growth factor (TGF)-b, IGFs I and II, (see Tables 1 and 2; Canalis, 1983). The end product of
and plasminogen activators have been proposed (Martin remodelling is the maintenance of a mineralized bone
and Ng, 1994; Mundy, 1994). Whether the activation of matrix and the major organic component of this matrix
osteoblasts begins simultaneously with osteoclast recruit- is type I collagen. The local factors are synthesized by
ment or at some later stage during lacunar development is skeletal cells and include growth factors, cytokines, and

FIG. 3. Bone remodelling (coupling). Diagrammatic representation of the coupling of osteoclastic bone resoprtion followed by osteoblastic bone formation. The
initial event involves the synthesis and release of matrix metalloproteinases (MMPs) by osteoblasts which are responsible for degrading the osteoid, exposing the
mineralized matrix which maybe chemotactic to the osteoclast. The osteoblast also directly stimulates osteoclast activity. During the resorption process growth
factors are released from the matrix which then activate osteoprogenitor cells. The osteoprogenitor cells mature into osteoblasts and ultimately replace the
resorbed bone. The mechanism by which osteoblasts are directed to form bone only in the resorption lacunae may be due to the presence of molecules such as
TGF-b and BMPs which are left behind during osteoclastic activity. Osteocytes communicate with one another via intercellular processes.
104 P. A. Hill Scientific Section BJO Vol 25 No. 2

TABLE 1 Hormones that regulate bone remodelling genase and gelatinase (Meikle et al., 1992). This facilitates
access of the osteoclasts to the underlying mineralized
Polypeptide hormones bone. The next step involves the recognition of extra-
Parathyroid hormone
Calcitonin
cellular bone matrix proteins via members of the integrin
Insulin superfamily of adhesion receptors, in particular the avb3
Growth hormone vitronectin receptor (Lakkakorpi et al., 1991). The vitro-
Steroid hormones nectin receptor binds to the extracellular matrix proteins,
1,25-Dihydroxyvitamin D3 such as osteopontin, at a tripeptide arginine-glycine-
Glucocoticoids aspartic acid (RGD) recognition site and appears essential
Sex steroids
Thyroid hormones
for inducing osteoclast polarization. The latter process
involves the formation of ruffled borders and clear zones,
two of the most characteristic features of osteoclasts
T A B L E 2. Growth factors that regulate bone remodelling (Roodman, 1996; Suda et al., 1996). The clear zone is an
organelle-free region of the cytoplasm that is rich in F-
Insulin-like growth factors (IGF) I and II actin filaments (actin rings). These actin rings in concert
Transforming growth factor-b (TGF-b) superfamily, including the bone with the integrin receptors and RGD containing-extra-
morphogenetic proteins (BMPs).
Fibroblast growth factors (FGF)
cellular proteins form focal adhesions or podosomes. The
Platelet-derived growth factors (PDGF) focal adhesions are responsible for the tight cell-to-
Selected cytokines of the interleukin (IL), tumour necroisis factor substratum interaction and seal the external space beneath
(TNF), and colony-stimulating factor (CSF) families. the cell where the ruffled border spreads and bone matrix
dissolution occurs. This extracellular space is called the
‘resorbing compartment’ or ‘resorption lacuna’. The third
prostaglandins. Growth factors are polypeptides that stage involves osteoclast activation at the surface of the
regulate the replication and differentiated function of cells. mineralized bone. This is probably initiated by the effects
Growth factors have effects on cells of the same class of local factors on cells of the osteoblast lineage rather than
(autocrine factors) or on cells of another class within the direct activation of osteoclasts and their precursors
tissue (paracrine factors). The presence of local factors is (Martin and Ng, 1994). In addition to the classical concept
not unique to the skeletal system, because non-skeletal that osteoblasts release an osteoclast activating factor(s),
tissues also synthesize, and respond to autocrine and recent findings have proposed a new concept that osteo-
paracrine factors. Growth factors are also present in the blasts may activate osteoclasts through a mechanism
circulation and may act as systemic regulators of skeletal involving cell-to-cell contact (Fuller et al., 1991). The next
metabolism, but the locally produced factors have more step involves the activated osteoclast resorbing the bone
direct and important functions in cell growth. Growth by the production of hydrogen ions (dissolution of
factors may play a critical role in the coupling of bone mineral) and proteolytic enzymes (degradation of organic
formation to bone resorption, and possibly in the patho- matrix) in the localized environment (hemivacuole) under
physiology of bone disorders. the ruffled border of the cell. Hydrogen ions are generated
within the cell by the enzyme carbonic anhydrase II
(Laitala and Vaananen, 1994) which is located in the
cytoplasm close to the ruffled border (Gay and Mueller,
Bone Resorption
1974). The critical importance of carbonic anhydrase II in
The bone resorption cascade involves a series of steps the osteoclast has been shown by studies in patients with
directed towards the removal of both the mineral and a congenital absence of this enzyme and osteopetrosis
organic constituents of bone matrix by osteoclasts, aided (Sly et al., 1985). The protons are extruded across the
by osteoblasts. The role of the osteoclast as a major ruffled border into the resorptive micro-environment by
resorbing cell, and its structure and biochemical properties a polarized vacuolar proton pump (Blair et al., 1989).
have been well characterized (Roodman, 1996). The first Degradation of the collagenous organic matrix follows
stage involves the recruitment and dissemination of dissolution of the mineralized matrix and involves two
osteoclast progenitors to bone. The osteoclast precursors major classes of enzymes, lysosomal cysteine proteinases
are clearly of haemopoietic origin (Walker, 1973) and such as cathepsin B, L and K (Hill et al., 1994a; Drake et al.,
related to the monocyte-macrophage lineage, but the point 1996), and MMPs including collagenase and gelatinase B
of divergence from that lineage is not established (Hill et al., 1993;1994b;1995).
(Hattersley et al., 1991). The progenitor cells are recruited Osteoclasts ultimately undergo apoptosis or pro-
from the haemopoietic tissues such as bone marrow and grammed cell death that is characterized by nuclear and
slenic tissues to bone via the circulating blood stream. They cytoplasmic condensation, and fragmentation of nuclear
proliferate and differentiate into osteoclasts through a DNA into nucleosomal-sized units. TGF-b, which blocks
mechanism involving cell-to-cell interaction with osteo- bone resorption can induce apoptosis in osteoclasts,
blast stromal cells (Suda et al., 1996). It seems likely that a while osteoclast-stimulatory factors, such as parathyroid
subpopulation of marrow and circulating monocytes are, in hormone, PTH, and 1,25-dihydroxyvitamin D3, inhibit
fact, determined pre-osteoclasts. The next step involves osteoclast apoptosis in vitro (Roodman, 1996). These data
the prepartion of the bone surface by removal of the suggest that regulation of osteoclast life span plays an
unmineralized osteoid layer by the lining osteoblasts, important role in the normal bone remodelling process to
which produce a variety of proteolytic enzymes, in either enhance or inhibit osteoclastic bone resorption.
particular the matrix metalloproteinases (MMPs), colla- Cytokines that enhance osteoclast activity do so in part by
BJO May 1998 Scientific Section Bone Remodelling 105

increasing osteoclast life span and factors that inhibit produced during the resorption process. Resorbing bone
osteoclast activity appear to induce osteoclast apoptosis, in has been shown to produce chemotactic factors for cells
addition to blocking osteoclast formation and bone with osteoblast characteristics in vitro (Mundy et al., 1982).
resorption. Since osteoclasts have a limited life span ;12·5 One mediator that may be responsible for this effect is
days, the progression of bone remodelling requires the TGF-b, since active TGF-b is released by resorbing bone
continual addition of osteoclasts precursors to maintain an cultures (Pfeilschifter and Mundy, 1987) and TGF-b is
existing team. Mononuclear osteoclast precursors need to chemotactic for bone cells (Pfeilschifter et al., 1990a,b).
be directed to their destination by a specific ‘homing’ Structural proteins such as collagen could also be involved,
signal. It has been suggested that the targeting of pre- since type I collagen and its fragments cause the same
osteoclasts for the initiation of remodelling is carried out effect (Mundy et al., 1982).
by lining cells under instruction from osteocytes, but that The second event involved in the formation phase of the
the targeting for progression is carried out by osteoclasts coupling phenomenon is proliferation of osteoblast
themselves. Evidence suggests that osteoclasts may release precursors. This is likely to be mediated by osteoblast-
paracrine factors, in particular interleukins (IL)-1, IL-6, derived growth factors and those growth factors released
and annexin-II that are concerned with osteoclast from bone during the resorption process. There are several
recruitment (Roodman, 1996). leading candidates which represent autocrine and
paracrine factors. These include members of the TGF-b
superfamily and several other growth factors that are
Reversal
sequestrated in bone matrix and stimulate osteoblast
After the maximum eroded depth has been achieved by proliferation, including IGF- I and II, fibroblast growth
the osteoclasts, there is a reversal phase that lasts ;9 days. factors (FGFs) and platelet-derived growth factor
The regulatory mechanisms that arrest osteoclastic activity (PDGF). Interestingly, these growth factors may have a
are poorly understood, but there are several possibilities. more subtle role to play in bone formation as they have
First, since the osteoclast has a limited life span, the cell recently been shown to prevent osteoblast apoptosis in
probably undegoes apoptosis following an extensive vitro (Hill et al., 1997).
episode of resorptive activity. Secondly, it has been The third event of the formation phase is the
demonstrated that the accumulation of calcium at high differentiation of the osteoblast precursor into the mature
concentrations in the resorption lacunae directly controls cell. Several of the bone-derived growth factors can
osteoclast activity causing both rapid cell retraction and in cause the appearance of markers of the differentiated
the longer term, an inhibiton of enzyme release and bone osteoblast phenotype, including expression of alkaline
resorption (Zaidi et al., 1990). A third possibility is that the phosphatase activity, type I collagen, and osteocalcin..
release of TGF-b or related peptides from the matrix Most prominent of these are IGF-I and bone morpho-
during the resorption process inactivates osteoclasts and genetic protein (BMP)-2, the latter is a member of the
attracts osteoblasts (Pfeilschifter and Mundy, 1987; TGF-b superfamily of polypeptides. The resorption
Pfeilschifter et al., 1990a,b). During the reversal phase, lacunae are usually repaired completely, although it is not
osteoclasts disappear and macrophage-like cells are seen known how this is achieved. The cessation of osteoblast
on the bone surface. These latter cells could release factors activity may be due to negative feedback inhibiton or the
that inhibit osteoclasts and stimulate osteoblasts. Macro- induction of osteoblast apoptosis by tumour necrosis
phages may also remove residual matrix since they are factor released from neighbouring marrow cells (Hill et al.,
richer in collagenase than the osteoclast. 1997).

Bone Formation Local regulation of bone remodelling

Bone formation results from a complex cascade of events Bone is a rich source of growth factors with important
that involves proliferation of primitive mesenchymal cells, actions in the regulation of bone formation and bone
differentiation into osteoblast precursor cells (osteo- resorption (Tables 1 and 2). Frequently, these local factors
progenitor, pre-osteoblast), maturation of osteoblasts, are synthesized by skeletal cells, although some cytokines
formation of matrix, and finally mineralization. Osteo- are secreted by stromal cells and by cells of the immune or
blasts converge at the bottom of the resorption cavity and haematological system, and as such they are present in the
form osteoid which begins to mineralize after 13 days at an bone microenvironment (Manologas and Jilka, 1995).
initial rate of ;1mm/day. The osteoblasts continue to form These factors are likely to be released locally from bone as
and mineralize osteoid until the cavity is filled. The time to it resorbs or by bone cells activated as a consequence of the
fill in the cavity at any given point on the surface is 124–168 resorption process. They may then act in a sequential
days in normal individuals (Ericksen et al., 1984). manner to regulate all of the cellular events required for
At the bottom of the cavity osteoblasts are plump and the formation of bone.
vigorous, they have tall nuclei, and they make a thick layer The TGF-b superfamily may be particularly important
of osteoid. The cells gradually flatten and become in the coupling that links bone formation to prior bone
quiescent lining cells. Some of the osteoblasts differentiate resorption (Fig. 3). It has been proposed that the following
into osteocytes and become embedded in the matrix. sequence of events occur during normal bone remodelling.
The initial event must be the chemotactic attraction of Bone resorption leads to the release of active TGF-b
osteoblasts or their precursors to sites of the resorption from bone (Pfeilschifter and Mundy, 1987) and exposure
defect. This is likely to be mediated by local factors of osteoblast precursors to active TGF-b causes pro-
106 P. A. Hill Scientific Section BJO Vol 25 No. 2

liferation. However this exposure to TGFb is transient Canalis, E. (1983)

and, as a consequence, the proliferating cells undergo The hormonal and local control of bone formation,
Endocrine Reviews, 4, 62–77.
differentiation and express BMPs. The latter are respon-
sible for an autostimulatory effect on osteoblasts and the Charles, P., Ericksen, E.F., Mosekilde, L., Melsen, F. and Jensen,
formation of mineralized nodules. Of course, it is unlikely F.T. (1987)
Bone turnover and balance evaluated by a combined calcium
that the TGF-b superfamily members are acting alone. balance and 47calcium kinetic study and dynamic
Other growth factors such as IGFs, FGFs, and PDGF are histomorphometry,
also likely to be having effects on osteoblast proliferation Metabolism: Clinical and Experimental, 36, 1118–1124.
and differentiation. These factors are all bone growth Drake, F.H., Robert, A.D., James, I.E., Conner, J.R., Debouck,
stimulants. There is much evidence to suggest that there C.C., Richardson, S., Lee-Rykaczewski, E., Coleman, L., Rieman,
are synergistic, as well as inhibitory interactions between D., Barthlow, R., Hastings, G. and Gowen, M. (1996)
the growth factors that act on osteoblasts. For example, Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed
TGF-b, FGFs, PDGF, BMPs, IGFs-I, and II may all in human osteoclasts,
influence osteoblasts directly, but also may modulate Journal of Biological Chemistry, 269, 15006–15009.
osteoblast responsiveness to these other growth factors Ericksen, E., Mosekilde, L. and Melsen, F. (1986)
(Massague, 1985; Roberts et al., 1985). The potential Trabecular bone remodelling and balance in primary
hyperparathyroidism,
interactions between these factors are complex, but it will
Bone, 7, 213–221.
be essential to unravel them to understand the local
control of bone formation. It is likely that the complicated Fuller, K., Gallagher, A. C. and Chambers, T. J. (1991)
Osteoclast resorption-stimulating activity is associated with
interactions between these factors released locally in osteoblast surface and/or extra cellular matrix,
active form as a consequence of the resorption process are Biochemical and Biophysical Research Communications, 181,
responsible for the carefully co-ordinated formation of 67–73.
new bone that occurs at these sites. Frost, H.M. (1964)
A potentially fruitful new approach to the problem of Dynamics of bone remodelling,
understanding the role of these growth factors in bone In: Bone Biodynamics, Frost H. M. (ed.), pp.315–333,
remodelling is to establish appropriate transgenic mouse Little Brown, Boston.
models to study the many paracrine growth and Frost, H. (1991)
differentiation factors that, based upon cell culture studies, A new direction for osteoporosis research: a review and proposal,
Bone, 12, 429–437.
have been implicated in bone remodelling (see Tables 1
and 2). The initial success of this approach can be seen with Gay, C. and Mueller, W. (1974)
Carbonic anhydrase and osteoclasts: localization by labelled
demonstration that transgenic mice over-expressing
autoradiography,
interleukin-4 develop osteoporosis due to impaired Science, 183, 432–434.
osteoblastic function (Lewis et al., 1993).
Hattersley, G., Kerby, J. and Chambers, T. (1991)
Generation of osteoclast precursors in multilineage hemopoietic
colonies,
Conclusions Endocrinology, 128, 259–262.
Hill, P. A., Reynolds, J. J. and Meikle, M. C. (1993)
Bone remodelling is a complex process involving a number Inhibition of stimulated bone resoprtion in vitro by TIMP-1 and
of cellular functions directed toward the co-ordinated TIMP-2,
resorption and formation of new bone. Bone remodelling Biochemica et Biophysica Acta, 1177, 71–74.
is regulated by systemic hormones and by local factors. Hill, P. A., Buttle, D., Jones, S., Boyde, A., Murata, M., Reynolds, J.
Hormones regulate the synthesis, activation, and effects J. and Meikle, M. C. (1994a)
of the local factors that have a direct action on cellular Inhibition of bone resorption by selective inactivators of cysteine
metabolism, and they modify the replication and differ- proteinases,
entiated function of cells of the osteoclast or osteoblast Journal of Cellular Biochemistry, 56, 118–130.
lineage. It is possible that the role of the hormones is to Hill, P. A., Murphy, J., Docherty, A., Hembry, R., Millican, T.,
provide tissue specificity for a given growth factor, because Reynolds, J. J. and Meikle, M. C. (1994b)
most of these factors are synthesized by a variety of The effects of selective inhibitors of matrix metalloproteinases
(MMPs) on bone resoprtion and the identification of MMPs and
skeletal and non-skeletal cells. TIMP-1 in isolated osteoclasts,
The rapidly accumulating new knowledge about the Journal of Cell Science, 107, 3055–3064.
multiple possible regulatory mechanisms within bone Hill, P. A., Docherty, A., Bottomley K., O’Connell, J. P., Morphy, J.
should aid the understanding of physiological bone R. Reynolds, J. and Meikle, M. C. (1995)
remodelling and also offer potential explanations for the Inhibition of bone resorption in vitro by selective inhibitors of
changes in bone turnover seen in a variety of disease states. gelatinase and collagenase,
This knowledge will be important in devising new Biochemical Journal, 308, 167–175.
therapeutic strategies to control bone formation and Hill, P. A., Tumber, A. and Meikle, M. C. (1997)
resorption based upon these novel regulatory mechanisms. Multiple extracellular signals promote osteoblast survival and
apoptosis,
Endocrinology, 138, 3849–3858.

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