Osteocytes as Dynamic Multifunctional
Cells
LYNDA F. BONEWALD
University of Missouri, School of Dentistry, Kansas City, Missouri, USA
ABSTRACT: The target of bone systemic factors and therapeutics has
been assumed to be primarily osteoblasts and/or osteoclasts and their
precursors. All the action with regard to bone modeling or remodeling
has been assumed to take place on the bone surface. In this scenario,
cells below the bone surface, that is, osteocyte, are considered to be inactive placeholders in the bone matrix. New data show osteocytes are
involved. In addition to the function of osteocytes translating mechanical strain into biochemical signals between osteocytes and cells on the
bone surface to affect (re)modeling, new functions are emerging. Osteocytes are exquisitely sensitive to mechanical strain in the form of shear
stress compared to osteoblasts or osteoclasts and communicate with each
other, with cells on the bone surface, and with marrow cells. Osteocytes
are able to move their cell body and their dendritic processes and appear
to be able to modify their local microenvironment. A novel function now
attributed to osteocytes includes regulation of phosphate metabolism.
Therefore, in addition to osteoblasts and osteoclasts, osteocytes are also
important for bone health.
KEYWORDS: osteocytes; mechanical load; E11/gp38; perilacunar matrix; Dmp1; Pex; FGF23
OSTEOCYTES AS ORCHESTRATORS OF BONE
ADAPTATION TO LOAD
Galileo in 1638 first suggested that the shape of bones is related to loading, but it was Julius Wolff in 1892 who proposed that bone accommodates
or responds to strain (for review see Ref. 1).1 Harold Frost proposed “Four
Windows” of mechanical strain: (1) disuse or lack of strain that results in bone
loss as occurs in astronauts, immobilized patients, and in the jaw bones of
edentulous patients; (2) homeostasis, where resorption equals formation and
is therefore necessary for the normal maintenance of bone mass; (3) modeling, where the application of load, such as exercise, results in an increase in
Address for correspondence: Lynda F. Bonewald, Ph.D., University of Missouri, School of Dentistry,
650 E 25th St., Kansas City, MO 64108. Voice: 816-235-2068; fax: 816- 235-5524.
[email protected]
C 2007 New York Academy of Sciences.
Ann. N.Y. Acad. Sci. 1116: 281–290 (2007). doi: 10.1196/annals.1402.018
281
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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
bone mass essentially through new bone formation; and (4) pathologic overload where extreme load is applied, such as occurs with new military recruits
and race horses where tremendous resorption is followed by formation.2 So
for decades, (if not centuries), the question has been asked as to how bone
responds to load or to unloading. A central theory for the past 30 to 40 years
is that the osteocyte is ideally located in bone to sense mechanical strain and
translate strain (or lack of) into biochemical signals to cells on the bone surface. However, this theory has been difficult to prove as osteocytes have been
relatively inaccessible.
The osteocyte is derived from the osteoblast. The osteoblast progenitor is
recruited to the bone surface where it differentiates into a polygonal matrixproducing cell. It is not clear why some of these cells are designated to become
osteocytes,3,4 but they make connections with existing embedded cells and then
are engulfed in osteoid where they are referred to as osteoid–osteocytes.5 Once
the matrix around them becomes mineralized they are referred to as mature
osteocytes. It is this cell embedded in mineralized matrix that has been referred
to as a passive, inactive cell acting as a placeholder in bone.
Osteocytes make up more than 90–95% of all bone cells in the adult skeleton, whereas osteoblasts compose less than 5% and osteoclasts less than 1%.
Osteocytes are viable for years, even decades, whereas osteoblasts live lifetimes of weeks and osteoclasts of days. The unique feature of osteocytes is
the formation of long dendritic processes that travel through small tunnels in
the bone matrix called canaliculi that connect osteocytes within their caves or
lacunae with cells on the bone surface. These processes have been shown to
extend into the bone marrow.6 Osteocytes are thought to send signals of both
bone resorption and bone formation, but this has not been validated. It has
been suggested that dying or dead osteocytes send signals of resorption7,8 and
recently it has been shown that a protein highly expressed in osteocytes called
sclerostin can target osteoblasts to inhibit bone formation.9 Osteocytes may act
as conductors with regard to directing both osteoclast and osteoblast activity,
as orchestrators of bone remodeling (see FIG. 1).
A major question in the field is how does the osteocyte sense mechanical
strain? It is thought that cells on the bone surface (lining cells, osteoblasts) are
most likely to be subjected to substrate strain, whereas osteocytes are more
likely to sense mechanical strain due to fluid flow shear stress. Osteocytes as
compared to osteoblasts are more responsive to fluid flow shear stress than to
other forms of mechanical strain, such as substrate stretching.10 It has been
proposed that osteocytes sense shear stress mainly along their dendritic processes, or along their dendritic processes and the cell body. Recently, it has
also been proposed that cilia may play a role in osteocyte mechanosensation.11
Preliminary data show that in vitro, osteocyte cell deformation correlates with
magnitude of shear stress, which in turn correlates with a biological response,
that of prostaglandin release (data not shown). It remains to be shown if this
occurs in vivo. PKD1 and 2, components of cilia, which are known to have
BONEWALD
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FIGURE 1. Simplified diagram of the potential roles of osteocytes in mechanotransduction. The osteocyte is in direct contact with cells on the bone surface and can extend
processes into the marrow space. The role of the lining cell in mechanotransduction remains
a mystery. The lining cells could be an intermediary for signaling or could be bypassed by
the osteocyte. ε = Normal Loading. With normal loading of the skeleton that maintains normal homeostasis, the osteocyte sends signals inhibiting osteoclast activity.46,47 Expression
of Dmp1, necessary for mineralization of osteoid, is increased in response to load.43 Osteocytes may also send signals to mesenchymal stem cells to differentiate into osteoblasts.48
Xε = Unloading. Upon immobilization, the osteocyte sends signals of resorption.46 These
signals may come from dying, apoptotic osteocytes7,49,50 or from viable cells.51 It has also
been shown that sclerostin expression is increased in response to unloading, potentially
inhibiting the activity of osteoblasts.52
a mechanosensory function in the kidney, are expressed in bone. Deletion of
PKD1 function results in animals with a bone defect.12 However, even though
cilia most likely do play an important role in osteocytes, it is not clear how and
if cilia are responsible for mechanotransduction.
FORMATION OF THE OSTEOCYTE LACUNOCANALICULAR
SYSTEM
We have asked the question, how is the lacunocanalicular network formed
and what is its function? The dogma has been that osteocytes form their dendrites through a passive process once the cell becomes surrounded by osteoid. This concept arose because the osteocyte has 30% of the cytoplasm of
a matrix producing osteoblast, therefore, the cytoplasm shrinks as the dendritic processes are left behind in the matrix. In a search for markers highly
expressed on osteocytes, the E11/gp38 molecule was found first in MLO-Y4
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osteocyte-like cells and also in early embedding osteocytes in bone but not in
cells on the bone surface.13,14 E11/gp38 is a 40 kDa transmembrane protein
thought to play a role in the formation of dendritic processes in various cell
types. Cells with extensive cellular projections, such as podocytes and type 1
alveolar lung cells, etc., express high amounts of E11/gp38. This membrane
molecule appears to play a role in dendrite elongation, as MLO-Y4 cells subjected to fluid flow shear stress elongate their processes and this elongation
was blocked by siRNA.14 Conditional deletion of this gene is a neonatal lethal
due to lung defects.15
In vivo loading resulted in elevation in both gene and protein expression of
E11/gp38, not only near the bone surface, but in deeply embedded bone in
response to loading.14 It was not clear why a molecule proposed to have a role
in dendrite formation would be increased in deeply embedded osteocytes—
cells thought to have their dendrites stationary and tethered to the walls of their
canaliculi.16,17 However, dynamic imaging of viable calvaria has shown that
osteocytes can extend and retract their dendritic processes.18 This suggests
that E11/gp38 could be involved in the extension of dendrites in osteocytes
embedded in bone in response to load. Observations using static data limit
our thinking and ability to form more accurate and novel hypotheses, whereas
dynamic imaging has opened a whole new area for investigation.
OSTEOCYTE MODIFICATION OF THEIR
MICROENVIRONMENT
Early pioneers in osteocyte biology noted from histological sections of bone
that there appeared to be increases of osteocyte lacunar size with various diseases or conditions.19,20 This led to the highly controversial theory of “osteocytic osteolysis” where it was proposed that osteocytes could remove bone.21
This theory fell out of favor because it was proposed that osteocytes could use
the same mechanisms as osteoclasts to remove bone. Recently, with the advent of new technology, such as atomic force microscopy and nanoindentation,
Raman spectrometry, and Scanning Acoustic Microscopy, data are emerging
to suggest that the perilacunar matrix surrounding the osteocyte is distinct
from the rest of the bone matrix. It appears that the perilacunar matrix has
a lower elastic modulus or is hypomineralized or “softer” than the surrounding matrix (data not published). Changes in perilacunar matrix could alter the
type or magnitude of strain sensed by the osteocyte and therefore modify their
responsiveness to load.22
The osteocyte can modify its microenvironment in response to environmental factors. It has been shown that administration of glucocorticoids appears
to enlarge or increase this perilacunar matrix and also leads to a significant
increase in lacunar size.23 Glucocorticoids not only appear to induce apoptosis
of osteoblasts and osteocytes,24 but appear to inhibit osteoclast activity.25 It
BONEWALD
285
has been proposed that osteocytes send signals to the osteoclast to initiate remodeling. If the osteoclast is prevented from responding to the osteocyte call
to resorb, then the osteocyte may become compromised and begin to remove
mineral from its lacunae and from its surrounding matrix. It is not clear at
this time what molecular mechanisms would be responsible. As the osteocyte
can remove mineral from its lacunae and perilacunar matrix, this cell may also
be able to modify the diameter of its canaliculi. Any change in canalicular
diameter would have an effect on the flow of the bone fluid. An increase in
canalicular diameter would decrease shear stress and a decrease in diameter
would increase shear stress. It has been shown that the number of canaliculi
per osteocyte increase with age.26,27 It is not known if the already embedded
osteocyte can generate new canaliculi or with bone remodeling with new bone
deposition, the new osteocytes have greater numbers of dendrites/canaliculi.
This could be one of the reasons why the aging skeleton is less responsive to
load.
ROLE OF OSTEOCYTES IN MINERAL METABOLISM
One can ascribe function to a cell type by identification of specific or selective markers of known function. Whereas E11/gp38 is a marker for early
osteocytes, sost/ sclerostin is a marker for late embedded osteocytes.28,29 Deletion of Sost in mice results in increased bone formation and mutation of Sost
in humans results in Sclerostosis.30 Sclerostin is a direct inhibitor of the Wnt
pathway through binding to Lrp5.31–33 The anabolic effect of PTH may be
through inhibition of Sost expression.34 These data support the hypothesis that
the osteocyte can regulate bone formation and mineralization by targeting the
osteoblast.
There are also three key molecules expressed in osteocytes that play a role
in phosphate homeostasis; highly expressed in osteocytes and an avian osteocyte specific marker, Dentin Matrix Protein 1, (Dmp1), and Pex/Phex, (Phosphate Regulating Neutral Endopeptidase on Chromosome X) both highly expressed in osteocytes,35,36 and FGF23, also expressed in osteocytes, but at
much lower levels.37 Deletion or mutation of either Pex or Dmp1 results in
hypophosphatemic rickets resulting from a dramatic elevation of FGF23 in
osteocytes.37,38 Hypophosphatemic rickets in humans is caused by inactivating mutations of Pex and autosomal recessive hypophosphatemia in humans
is due to mutations in Dmp1, both resulting in elevated circulating levels of
FGF23.38–40 FGF23 is a phosphaturic factor that prevents reabsorption of Pi
by the kidney leading to hypophosphatemia (see FIG. 2).
Dmp1 appears to have functions in addition to regulation of FGF23 expression. Dmp1 has been shown to have a nuclear localization sequence,41 the
secreted protein is highly phosphorylated, and recombinant Dmp1 nucleates
apatite.42 This suggests that Dmp1 could function intracellulary to regulate
transcription and extracellulary to regulate mineralization of osteoid. Dmp1
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FIGURE 2. Simplified diagram of the interactions between Dmp1, Phex, and FGF23,
all shown to be expressed in osteocytes. Both Dmp1 and Phex appear to downregulate
FGF23 expression, which in turn allows reabsorption of phosphate by the kidney thereby
maintaining sufficient circulating phosphate to maintain bone mineral content (A). In the
absence of either Dmp1 or Phex, FGF23 is highly elevated in osteocytes leading to phosphate
excretion by the kidney thereby lowering circulating phosphate leading to osteomalacia and
rickets (B). Osteocytes appear to play a major role in mineral homeostasis.
BONEWALD
287
null mice fed a high phosphate diet showed rescue of the length of the long
bones, but not a full rescue of the osteomalacia.38 Unmineralized osteoid surrounding osteocytes was still present in these animals. This suggests that Dmp1
has both a systemic and a local function. As the length of the bones in the
Dmp1 null is rescued by high phosphate diet, this suggests that Dmp1 regulates FGF23 expression, which in turn systemically regulates phosphate. As
the osteomalacia is not completely corrected, this suggests that Dmp1 regulates mineralization of bone osteoid. Based on these observations we have
proposed that the osteocyte network can function as an endocrine gland to
regulate phosphate homeostasis. As both Dmp1 and Phex are regulated by
mechanical loading,43–45 it will be important to determine if skeletal loading
can play a role in mineral and phosphate metabolism.
ACKNOWLEDGMENT
This work was supported by NIH NIAMS PO1 AR46798.
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