Advancing our understanding of osteocyte cell biology
Identifieur interne : 004773 ( Istex/Corpus ); précédent : 004772; suivant : 004774Advancing our understanding of osteocyte cell biology
Auteurs : Jeffrey J. Dayong Guo ; Lynda F. BonewaldSource :
- Therapeutic Advances in Musculoskeletal Disease [ 1759-720X ] ; 2009-12.
Abstract
Osteocytes were the forgotten bone cell until the bone community could become convinced that these cells do serve an important role in bone function and maintenance. In this review we trace the history of osteocyte characterization and present some of the major observations that are leading to the conclusion that these cells are not passive placeholders residing in the bone matrix, but are indeed, major orchestrators of bone remodeling.
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DOI: 10.1177/1759720X09341484
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<front><div type="abstract" xml:lang="en">Osteocytes were the forgotten bone cell until the bone community could become convinced that these cells do serve an important role in bone function and maintenance. In this review we trace the history of osteocyte characterization and present some of the major observations that are leading to the conclusion that these cells are not passive placeholders residing in the bone matrix, but are indeed, major orchestrators of bone remodeling.</div>
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<abstract><p>Osteocytes were the forgotten bone cell until the bone community could become convinced that these cells do serve an important role in bone function and maintenance. In this review we trace the history of osteocyte characterization and present some of the major observations that are leading to the conclusion that these cells are not passive placeholders residing in the bone matrix, but are indeed, major orchestrators of bone remodeling.</p>
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Review
Advancing
our understanding of osteocyte cell biology
SAGE Publications, Inc.
200910.1177/1759720X09341484
© The Author(s),
2009.
2009
The Author(s)
Dayong Guo
650 E 25th Street, School of Dentistry, Department of
Oral Biology, University of Missouri at Kansas City, Kansas City, MO 64108,
USA, bonewaldl@umkc.edu
Lynda F.Bonewald
University of Missouri, Kansas City, MO, USA
Osteocytes were the forgotten bone cell until the bone community could
become convinced that these cells do serve an important role in bone function
and maintenance. In this review we trace the history of osteocyte characterization
and present some of the major observations that are leading to the conclusion
that these cells are not passive placeholders residing in the bone matrix,
but are indeed, major orchestrators of bone remodeling.
osteocytes
bone remodelling
parathyroid hormone
Osteocyte
morphology and function Osteocytes are stellate-shaped cells within the mineralized
bone matrix that comprise 90–95% of all bone cells, therefore, they
are the most abun- dant bone cell in the adult skeleton. The morphol- ogy
of the osteoblast, a plump polygonal cell, changes dramatically as it becomes
an osteocyte with reduced cytoplasm and numerous dendritic processes. Osteocytes
are encased within lacunae, within the mineralized bone matrix, and are con-
nected and networked to each other via dendrites that travel through canaliculi
(Figure 1). The extracellular fluid in the lacunar-canalicular space is believed
to be able to stimulate osteocytes by mechanical loading-induced fluid flow
shear- stress [Weinbaum et al. 1994]. Due to the inaccessible nature of osteocytes
in bone matrix, knowledge of their functions is still incomplete. Their special
morphology implies multiple potential roles as mechanosensors and communicators.
Years ago, sensitivity to mechan- ical stress was discovered in osteocytes
by the rapid emission of prostaglandin (PGE2) within 1 hour of fluid flow,
compared to a much slower response in osteoblasts or fibroblasts [Klein- Nulend
et al. 1995b]. Localized on both osteo- cytes and osteoblasts, functional
gap-junctions are now known to be the channels through which osteocytes release
their PGE2 after fluid flow, and further upregulate connexin (Cx43) through
PGE2 EP-4 receptor and the PKA path- way in an autocrine manner [Cherian et
al. 2003]. Recent studies of hemichannels also provide an alternative mechanism
of release of PGE2 to the extracellular space [Cherian et al. 2005; Jiang
and
Cherian,
2003]. Osteoblasts, osteoclasts, and bone-marrow cells could potentially be
regulated through gap junctions and hemichannels by signal molecules sent
from osteocytes [Heino et al. 2004; Ilvesaro and Tuukkanen, 2003; Zhao et
al. 2002; Yellowley et al. 2000]. Other channels and signaling molecules have
been reported in osteocytes. Nitric oxide (NO) was suggested as another mechanical
mediator corre- lating with PGE2 release from osteocytes [Klein- Nulend et
al. 1995a], which was supported by the detection of endothelial nitric oxide
synthase (eNOS) in osteocytes [Zaman et al. 1999]. ATP and intracellular calcium
can also be released from osteocytes in response to extracellular cal- cium
or mechanical stimulation [Genetos et al. 2007; Kamioka et al. 1995]. Voltage-operated
cal- cium channels (VOCC) that can be regulated by hormones, were shown to
be expressed in osteo- blasts and osteocytes [Shao et al. 2005; Gu et al.
2001b]. Expression of potassium (K+) channels during differentiation from
osteoblasts to osteo- cytes leads to different K+ currents between osteocytes
and osteoblasts [Gu et al. 2001a]. Because of their contribution to the maintenance
of the cell-membrane potential, and their fast response in 20 msec, K+ channels
and other ion channels may be involved in the earliest initiation of mechanical
response in osteocytes. Expression of sodium-dependent glutamate transporters
also supports the concept that a mechanism similar to neural synapse may exist
in the osteocytes [Mason and Huggett, 2002]. Polycystins (PKD1, 2) have been
shown to form calcium-permeable channels in response to tubular flow in primary
cilia of
88
Figure
1. Osteocyte lacuno-canalicular network. (a) Scanning electron micrograph
of an acid-etched resin- embedded mouse ulna revealing a complex lacuno-canalicular
system in bone. (b) In this diagram of osteoblast to osteocyte differentiation,
the early osteoid osteocyte has reduced in cell body by around 30% and by
the time it becomes a mature osteocyte, by 70%. The dendrites remain connected
to cells on the bone surface mostly likely through gap junctions. Hemichannels
are also present on the body and dendritic processes of osteocytes to release
small signaling molecules in response to shear stress by the surrounding bone
fluid.
kidney
cells [Nauli et al. 2003], which could be another mechanical sensor pathway
in osteocytes since cilia have been observed on the surface of osteocytes
[Xiao et al. 2006; Tonna and Lampen, 1972]. Mechanical strains could be converted
to biolog- ical signals through cytoskeletal deformation in the cytoplasm.
Based on the abundance of actin filaments in osteocytes, it is reasonable
to propose their direct involvement in the mechanical response. An above-threshold
fiber-strain can
induce
actin fiber-disassembly in osteoblasts [Sato et al. 2005]. Certain protein
kinases, such as Rho, may mediate this process, [Sarasa-Renedo et al. 2006;
Gerthoffer, 2005] however, their reg- ulation of actin dynamics have not been
reported in osteocytes. Since vimentin has been observed to be adjacent to
gap junctions in osteocytes and osteoblasts [Shapiro et al. 1995], it is reasonable
to hypothesize that the higher mechanical sensi- tivity of osteocytes compared
to osteoblasts could be caused by their distinctive cytoskeleton config- uration.
Recent evidence further revealed that
89
cytoskeletal
disruption in osteocytes inhibited PGE2 response to fluid flow, while in osteoblasts
it was enhanced [Mcgarry et al. 2005]. Residing within bone matrix means reduced
nutrition and oxygen, and no space for prolifera- tion of the cell. Therefore,
osteocytes maintain the adaptive features of no cell-division, a long life-
span, and resistance to apoptosis. Several apopto- sis suppressors have been
reported to support osteocyte survival under adverse conditions or apoptotic
inducement. During the differentiation of osteoblasts to osteocytes, matrix
metalloprotei- nases (MMPs) safeguard the cells from apoptosis [Karsdal et
al. 2004]. Estrogen protects osteocytes against glucocorticoid-induced apoptosis
[Gu et al. 2005]. Parathyroid harmone (PTH) prevents dexamethasone-induced
apoptosis through PTH receptors expressed in osteocytes [Bringhurst, 2002].
Through expression of its receptor in osteo- blasts and osteocytes, CD40 ligand
blocks apop- tosis induced by multiple apoptotic factors [Bonewald, 2004;
Ahuja et al. 2003]. Deletion of a hypoxia protective gene, klotho, influenced
spa- tial distribution of osteocytes, and accelerated aging and apoptosis
of the cells [Suzuki et al. 2005]. Interestingly, mechanical stimulation inhi-
bits, and disuse promotes osteocyte apoptosis [Plotkin et al. 2005; Bakker
et al. 2004]. Flow of bone fluid through the lacuno-canalicular system Deformation
of calcified tissues is difficult under physiological loads. Strain in healthy
bones of adult animals and humans was quantitatively measured to be less than
0.2% [Burr et al. 1996; Rubin, 1984], adequate to induce bone formation in
vivo [Forwood, 1996]. However, in vitro studies showed that much higher deformations
were needed to stimulate cultured osteoblast cells for any response [Murray
and Rushton, 1990]. A well-known model proposed that osteocytes can sense
the extracellular lacuno-canalicular fluid flow derived from the strain of
physiological loads on bone [Cowin et al. 1991]. According to related experiments
and calculations, a strain of 0.1% on bone would be magnified into a canali-
cular-fluid flow shear-stress of approximately 8–30 dyn/cm2 because
of the narrow canalicular space [Weinbaum et al. 1994]. This magnitude of
flow is adequate to induce PGE2, ATP and NO release from osteocytes [Genetos
et al. 2007; Westbroek et al. 2000; Klein-Nulend et al. 1995a, b]. Fluid flow
can also promote material exchange through the lacuno-canalicular network.
The
signal molecules can be carried to cells on the bone surface, near the loaded
area of bone. More sufficient nutrition and oxygen can also be pro- vided
to osteocytes in the loaded area [Kufahl and Saha, 1990]. This may be one
of the reasons that mechanical loading has been shown to inhibit osteocyte
apoptosis [Plotkin et al. 2005], and disuse promoted apoptosis [Bakker et
al. 2004]. The osteocyte’s response to canalicular fluid flow may play
an important role in the regulation of bone remodeling. To understand the
function of osteocytes, it is necessary to study the transcrip- tional and
translational changes in osteocytes sub- jected to mechanical loading such
as fluid-flow shear-stress. Osteocyte cell models Compared to osteoblasts
and osteoclasts with clearly identified roles, little is known concerning
osteocyte function. This is in part due to the dif- ficulties in isolating
sufficient numbers of osteo- cytes from the mineralized bone-matrix and maintaining
their differentiated function in vitro. Primary cultures of osteocyte-like
cells have been prepared by sequential alternating digestions of fetal rat
and chick calvaria with collagenase and EDTA [Van Der Plas and Nijweide, 2005;
Mikuni-Takagaki et al. 1996]. A population enriched for osteocytes can be
released in late digests after the removal of fibroblasts and osteo- blasts.
However, the yields of osteocytes are low. There has been a lack of cell lines
to represent osteocytes in vitro. Previously, our group had developed an osteocyte-like
cell line, MLO-Y4 [Kato et al. 1997]. This cell line was derived from a transgenic
mouse in which the immortaliz- ing T-antigen was expressed under control of
the osteocalcin promoter. MLO-Y4 cells exhibit properties of osteocytes including
high expression of osteocalcin, connexin 43, and the antigen E11/ gp38, while
alkaline phosphatase is low. Also, the dendritic morphology of MLO-Y4 cells
is similar to that of primary osteocytes. Osteocyte markers Osteocyte specific
proteins start to be expressed when osteoblasts differentiate into osteocytes
(Figure 2). E11/gp38 and CD44 have been reported to be expressed in osteocytes
during the formation of dendritic processes [Zhang et al. 2006; Kato et al.
1997], and physical association of the two proteins may be essential for the
func- tion of E11/gp38 [Ohizumi et al. 2000]. It is believed that organized
expression of tubulin, vimentin, and actin in cell bodies and dendrites
90
Figure
2. Markers of osteoblasts and osteocytes. Distinctive markers have been identified
during the differ- entiation of osteoblasts to osteocytes. Osteoblasts are
differentiated from mesenchymal stem cells expressing Stro 1, CD29, CD105
and CD166. Markers for osteoblasts include Cbfa1 and osterix for early osteoblasts,
alkaline phosphatase and collagen for differentiating osteoblasts and osteocalcin
for the mature osteoblast. Markers recently identified for osteocytes include
E11/gp38, MEPE, PHEX, DMP1 and sclerostin. E11/gp38, MEPE and PHEX start to
be expressed in late osteoblasts differentiating into osteocytes. DMP1 is
expressed in early embedding osteocytes. Sclerostin is only expressed in deeply-embedded
late osteocytes.
of
osteocytes are crucial to maintaining their cytoskeletal shape which is distinct
from the polygonal osteoblast [Tanaka-Kamioka et al. 1998]. Furthermore, dramatic
differences in dis- tribution of actin-binding proteins, such as fim- brin,
villin, filamin and spectrin, have been described accompanying the differentiation
of osteoblasts to osteocytes [Kamioka et al. 2004]. A recent study of green
fluorescent protein (GFP)-labeled osteocytes in calvaria [Kalajzic et al.
2004] also dynamically recorded frequent extension and retraction of dendrites,
indicating constant changes of the embedded osteocyte cytoskeleton [Dallas
et al. 2009]. E11/gp38/pdpn highly expressed in early embedding osteoid osteocytes
E11, also called podoplanin, OTS-8, gp38 or PA2.25, was first detected on
the cell surface of osteocytes in rat bone[Schulze et al. 1999; Wetterwald
et al. 1996], and odontoblasts in rat tooth [Schwab et al., 1999]. It is also
expressed in type I cells of rat lung and other tissues of brain, kidney,
lymphatic tissue, and skin. E11/gp38 shares 87% cDNA homology between mouse
and rat, and with similar distribution in tissues of the two species. Immunohistochemical
staining of mouse bones indicated that E11/ gp38 was strongly expressed in
the newly embedded osteoid-osteocytes, but not in chon- drocytes, osteoblasts
or bone-marrow cells.
Expression
was decreased in deeply embedded osteocytes [Zhang et al. 2006]. It was reported
that E11/gp38 colocalizes with ERM (ezrin, radixin and moesin), and coimmu-
noprecipitated with ezrin and moesin in keratino- cytes [Scholl et al. 1999].
In fibroblasts, ERM proteins crosslink actin and plasma membranes via the
N-terminus of CD44 [Yonemura et al. 1998; Tsukita et al. 1997] which is a
plasma- membrane protein associating with E11/gp38 [Ohizumi et al. 2000].
The binding of ERM pro- teins with the cytoplasmic tail of E11/gp38 trig-
gered further downstream activation of RhoA GTPase to regulate actin cytoskeleton
in kidney- epithelial cells [Martin-Villar et al. 2006]. It was recently revealed
that the morphology and function of osteocytes could be related to E11/ gp38,
especially dendrite formation and response to mechanical stimulation. Application
of fluid flow shear-stress on osteocyte-like MLO-Y4 cells increased the number
and length of dendrites as well as the mRNA level of E11/gp38 [Zhang et al.
2006]. The response was blocked by small inter- fering RNA against E11/gp38
mRNA. Similarly, ulnae from heterozygote E11+/– with one allele replaced
by lacZ showed increased X-gal staining after mechanical loading. However,
the E11/ gp38 knockout failed to generate viable homozy- gotes for a postnatal
functional study because the newborns die at birth. This is possibly due to
91
respiratory
failure when E11/gp38 is depleted from the type I cells in the lung [Schacht
et al. 2003]. Therefore, a targeted deletion of E11/ gp38 in vivo in osteocytes
is needed to reveal its function in the skeleton. Role of osteocyte-specific/highly-selective
proteins in mineral metabolism The osteocyte lacuno-canalicular system should
be viewed as an endocrine organ regulating phos- phate metabolism, as several
osteocyte-specific or highly-selective proteins have been shown to func- tion
in phosphate metabolism (Table 1). Once the osteoblast begins to embed in
osteoid, molecules such as Dmp1, Phex, and Mepe are expressed. Dentin Matrix
Protein 1, (Dmp1), and Pex/ Phex, (phosphate regulating neutral endopepti-
dase on chromosome X) are both highly expressed in osteocytes [Toyosawa et
al. 2001]. Deletion or mutation of either Pex or Dmp1 results in hypo- phosphatemic
rickets due to a dramatic elevation of FGF23 in osteocytes [Feng et al. 2006;
Liu et al. 2006]. Elevated circulating levels of FGF23 are responsible for
the human conditions of Autosomal Dominant Hypophosphatemic Rickets caused
by inactivating mutations of Pex and Autosomal Recessive Hypophosphatemia
caused by mutations in Dmp1 [Feng et al. 2006; Lorenz-Depiereux et al. 2006;
The Hyp Consortium, 1995]. FGF23 is a phosphaturic factor that prevents reabsorption
of Pi by the kidney leading to hypophospahtemia. Dmp1 may have multiple functions.
Unmineralized osteoid continues to surround osteocytes in Dmp1-null mice fed
a high-phosphate diet in spite of a rescue of the length of the long bones
[Feng et al. 2006]. These observations suggest that Dmp1 has both a systemic-
(regulation of FGF23) and a local-function (regulation of osteo- cyte perilacunar
mineralization). Based on the fact that osteocytes can express Phex, Dmp1,
Table
1. Proteins highly expressed in osteocytes.
and
FGF23, we have proposed that the osteocyte network can function as an endocrine
gland to regulate phosphate homeostasis. The role of MEPE (matrix extracellular
phospho- glycoprotein) in the regulation of phosphate metabolism is less clear.
MEPE, also known as osteoblast/osteocyte factor 45, is highly-expressed in
osteocytes as compared to osteoblasts. The pro- teases, Cathepsin D or B,
have been shown to cleave MEPE, releasing the C-terminal phospho- protein
region, called the ASARM peptide, which has been shown to be a potent inhibitor
of mineralization in vitro [Bresler et al. 2004] and high-ASARM peptide production
by osteocytes correlates to an osteomalacia-type phenotype in the hyp mouse
model. Deletion of this gene in mice, results in increased bone formation
and bone mass and resistance to age-associated trabe- cular bone loss [Gowen
et al. 2003]. As terminally differentiated osteoblasts become embedded in
the bone matrix, MEPE expression increases, therefore osteocytes act directly
on osteoblasts through MEPE to inhibit their bone forming activ- ity. The
unraveling of the interactions between these molecules and their fragments
should lead to insight into the function of osteocytes. Sost/sclerostin Research
on sclerosteosis and van Buchem disease revealed mutations of a new gene named
Sost responsible for the defects in these diseases [Balemans et al. 2001;
Brunkow et al. 2001]. Patients with mutant Sost showed high bone mass [Balemans
et al. 2005]. Its protein, termed sclerostin, is highly expressed in mature
osteocytes and acts as a negative regulator of bone formation [Poole et al.
2005]. It was originally considered to be a bone morphogenetic protein (BMP)
antago- nist but later discovered to be involved in the Wnt pathway as an
antagonist against LRP5, a positive
92
regulator
of bone mass [Li et al. 2005; Van Bezooijen et al. 2004]. Sclerostin is upregulated
by osterix and runx-2 [Ohyama et al. 2004] which are downstream of BMP signaling
path- ways, indicating a negative feedback preventing excessive bone formation
[Sutherland et al. 2004]. PTH has been reported to function as an inhibitor
of sclerostin which partially explains the anabolic effect of PTH on bone
formation [Silvestrini et al. 2007; Keller and Kneissel, 2005]. Similarly,
another bone formation stimula- tor, mechanical loading, has been reported
to reduce sclerostin expression [Robling et al. 2006]. An antibody to sclerostin
is being consid- ered as a new drug against postmenopausal osteo- porosis
[Lewiecki, 2009; Li et al. 2008] because of its specificity and its anabolic
effect on bone formation. Osteocytes as orchestrators of bone resorption and
formation After a review of the osteocyte markers as outlined above, it is
clear that osteocytes can regulate bone formation, and there is also evidence
that osteo- cytes regulate osteoclastic bone resorption. The osteocyte-like
cell line MLO-Y4 supports osteo- blast differentiation [Heino et al. 2002],
and sur- prisingly, mesenchymal stem-cell differentiation [Heino et al. 2004].
In contrast, isolated avian- osteocytes can support osteoclast formation and
activation [Tanaka et al. 1995] as can the osteo- cyte-like cell line, MLO-Y4
[Zhao et al. 2002] both in the absence of any osteotropic factors, unlike
any other stromal or osteoblast cell. Kogianni and colleagues found that these
cells produce ‘apoptotic bodies’ with the capacity to recruit
osteoclasts due to the expression of RANKL on their surface [Kogianni et al.
2008]. Together these data suggest that osteocytes can act as orchestrators
of bone remodeling. Not only do viable osteocytes send signals of resorption,
osteocytes appear to also support osteoclast activation and formation through
their death, whether apoptotic or necrotic. Osteocyte apoptosis occurs at
sites of microdamage where they send targeted signals for osteoclastic removal
of damaged bone. Verborgt and co-workers mapped the expression of anti-apoptotic
and pro-apoptotic molecules in osteocytes surround- ing microcracks and found
that pro-apoptotic molecules are elevated in osteocytes immediately at the
microcrack locus, whereas anti-apoptotic molecules are expressed 1–2
mm from the micro- crack [Verborgt et al. 2000]. Therefore those
osteocytes
that do not undergo apoptosis are pre- vented from doing so by protective
mechanisms while those destined for removal by osteoclasts undergo apoptosis.
Targeted ablation of osteo- cytes was performed using the 10 kb Dmp1 pro-
moter to drive the diptheria toxin receptor in mice [Tatsumi et al. 2007].
Injection of a single dose of diphtheria toxin eliminated approximately 70%
of osteocytes in cortical bone in these mice leading to dramatic osteoclast
activation. This suggests that viable osteocytes are necessary to prevent
osteoclast activation and maintain bone mass. In summary, it appears that
osteocytes can support mesenchymal cell-differentiation, osteoblast for- mation,
and osteoclast resorption, thereby posses- sing the unique capacity to regulate
all phases of bone remodeling. Osteocyte genomics and proteomics for the future
Comprehensive genomic and proteomic profiling is needed to explore the details
of osteocyte mor- phology, function as mechanosensors, their viabi- lity,
and their regulation of other cells. Recently, transcriptional level screening
with mRNA micro- arrays has been practiced to compare global pat- terns of
osteocytes and osteoblasts [Yang et al. 2004]. At the transcription level,
microarray results showed major differences in actin cytoske- leton and cell-communication
systems. Genomic changes of osteocytes after mechanical loading were also
studied [Yang et al. 2004]. However, mRNA transcripts do not always correlate
with corresponding protein abundance, or with post-translationally modified
(PTM) forms. Therefore, it is not enough to understand the function of osteocytes
only at the transcription level. Proteins are vital molecules because they
directly determine structure and function of the cell, and do the ‘work’
of the cell. Proteomics is the large-scale study of proteins which is usually
considered the next step after genomic studies. Proteomics is more complicated
than genomics because of the variations resulting from alterna- tive splicing,
translation regulations, post-transla- tional modifications, and different
fragmentations and degradations. These processes potentially change the function
and activity of a protein. Therefore, proteomics provides directly relevant
information regarding protein identification and potential structure and function.
Therefore, a proteomic comparison and alternative validations are necessary
not only to support the prior discov- eries, but also to reveal new targets
responsible for novel functional mechanisms in osteocytes.
93
Identification
of osteocyte-selective proteins should allow us to identify and understand
more about the function of osteocytes. Proteomic changes in fluid flow treated
osteocytes should help us understand their role as mechanical sen- sors. This
knowledge would form a foundation for understanding and treatment of defective
osteo- cyte-related diseases. Acknowledgement This work was supported by NIH
NIAMS PO1 AR46798. Conflict of interest statement None declared.
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<mods version="3.6"><titleInfo lang="en"><title>Advancing our understanding of osteocyte cell biology</title>
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<titleInfo type="alternative" lang="en" contentType="CDATA"><title>Advancing our understanding of osteocyte cell biology</title>
</titleInfo>
<name type="personal"><namePart type="family">Dayong Guo</namePart>
<affiliation>University of Missouri, Kansas City, MO, USA</affiliation>
<affiliation>University of Missouri, Kansas City, MO, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">Lynda F.</namePart>
<namePart type="family">Bonewald</namePart>
<affiliation></affiliation>
<affiliation>E-mail: bonewaldl@umkc.edu</affiliation>
<affiliation>School of Dentistry, Department of Oral Biology, University of Missouri at Kansas City, Kansas City, MO 64108, USA, bonewaldl@umkc.edu</affiliation>
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<dateIssued encoding="w3cdtf">2009-12</dateIssued>
<copyrightDate encoding="w3cdtf">2009</copyrightDate>
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<abstract lang="en">Osteocytes were the forgotten bone cell until the bone community could become convinced that these cells do serve an important role in bone function and maintenance. In this review we trace the history of osteocyte characterization and present some of the major observations that are leading to the conclusion that these cells are not passive placeholders residing in the bone matrix, but are indeed, major orchestrators of bone remodeling.</abstract>
<subject><genre>keywords</genre>
<topic>osteocytes</topic>
<topic>bone remodelling</topic>
<topic>parathyroid hormone</topic>
</subject>
<relatedItem type="host"><titleInfo><title>Therapeutic Advances in Musculoskeletal Disease</title>
</titleInfo>
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<identifier type="ISSN">1759-720X</identifier>
<identifier type="eISSN">1759-7218</identifier>
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<identifier type="PublisherID-hwp">sptab</identifier>
<part><date>2009</date>
<detail type="volume"><caption>vol.</caption>
<number>1</number>
</detail>
<detail type="issue"><caption>no.</caption>
<number>2</number>
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<extent unit="pages"><start>87</start>
<end>96</end>
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<identifier type="DOI">10.1177/1759720X09341484</identifier>
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