Download PPARs in Bone: The role in bone cell differentiation and regulation

Curr Osteoporos Rep (2010) 8:84–90
DOI 10.1007/s11914-010-0016-1
PPARs in Bone: The Role in Bone Cell Differentiation
and Regulation of Energy Metabolism
Beata Lecka-Czernik
Published online: 1 April 2010
# Springer Science+Business Media, LLC 2010
Abstract Obesity, diabetes, and osteoporosis are major
public health concerns. Current estimates indicate that the
US population consists of 25% obese, 30% diabetic and
prediabetic, and, among the elderly, 50% of all osteoporotic
individuals. Mechanistically, these pathologies share
several features including common regulators of bone
homeostasis and energy metabolism. Peroxisome
proliferator-activated receptors (PPARs) represent a family
of proteins that control energy turnover in adipose, liver,
and muscle tissue. These proteins also control bone
turnover and regulate bone cell differentiation. Recent
evidence suggests that bone is an organ integral to energy
metabolism not only with respect to energy storage, but
also as an organ regulating systemic energy homeostasis. In
this article, we review current knowledge on the role of
PPARs in bone metabolism and bone cell differentiation.
We also discuss the role of bone fat in modulation of bone
marrow microenvironment and its possible contribution to
the systemic regulation of energy metabolism.
Keywords Bone metabolism . Bone cell differentiation .
PPARs . Energy metabolism . Mesenchymal stem cells .
Thiazolidinediones
Introduction
Recent advances in understanding of the role of bone in the
systemic regulation of metabolism indicate that bone is an
B. Lecka-Czernik (*)
Departments of Orthopaedic Surgery and Physiology and
Pharmacology, Center for Diabetes and Endocrine Research,
University of Toledo Medical Center,
3000 Arlington Avenue,
Toledo, OH 43614, USA
e-mail: [email protected]
integral part of energy metabolism. It has become evident
that bone cells of the mesenchymal lineage, osteoblasts and
adipocytes, determine bone metabolic function. Osteoblasts
produce osteocalcin, a bone-specific hormone that has a
potential to regulate both insulin production in the pancreas
and adiponectin production in fat tissue [1•, 2]. Marrow
adipocytes, which exhibit many features of extramedullary
fat, store significant quantities of fat and produce adipokines (cytokines produced by adipose tissue), which play a
role in the regulation of energy metabolism. Both osteoblasts and marrow adipocytes originate from marrow
mesenchymal stem cells (MSCs) and their differentiation
is under the control of systemic, as well as, intrinsic factors,
including peroxisome proliferator-activated receptor
(PPAR) transcription factors [3, 4•].
PPARs are transcription factors that belong to the
superfamily of nuclear receptors. Other members of this
family include retinoic acid, estrogen, thyroid, vitamin D,
and glucocorticoid receptors, and several other proteins
involved in xenobiotic metabolism. PPARs act on DNA
response elements as heterodimers with the retinoid X
receptor. Their natural activating ligands are lipid-derived
substrates. The family of PPARs is represented by three
members: PPAR-α, PPAR-δ, and PPAR-γ. They play an
essential role in energy metabolism; however, they differ in
the spectrum of their activity—PPAR-γ regulates energy
storage, whereas PPAR-α and PPAR-δ regulate energy
expenditure [5].
The PPARs possess the canonical domain structure
common to other nuclear receptor family members,
including the amino-terminal AF-1 transactivation domain,
followed by a DNA-binding domain, and a dimerization
and ligand-binding domain with a ligand-dependent transactivation function AF-2 located at the carboxy-terminal
region [6]. Upon ligand binding and formation of the
transcriptional complex, which includes retinoic receptor
Curr Osteoporos Rep (2010) 8:84–90
heterodimerization partner and assembly of coactivator
proteins, PPARs facilitate transcription by binding to
cis-acting peroxisome proliferator response element in the
gene regulatory region. The PPARs’ transcriptional specificity is determined by a ligand-specific interaction, which
introduces allosteric alterations in the AF-2 domain and
recruitment of coactivators in the PPAR type– and cell
type-specific manner [6, 7]. We review the metabolic
activities of all three PPARs and the status of current
knowledge regarding their role in bone cell differentiation
and the maintenance of bone homeostasis.
PPAR-γ
PPAR-γ is an essential regulator of lipid, glucose, and
insulin metabolism [7]. PPAR-γ represents a key transcription factor for adipocyte differentiation and for the
maintenance of the adipogenic phenotype. This receptor is
expressed in mice and humans as two different isoforms,
PPAR-γ1 and PPAR-γ2, due to alternative promoter usage
and alternative splicing [8]. In humans, PPAR-γ2 differs
from PPAR-γ1 by the presence of 28 amino acids (30
amino acids in rodents) located on the AF-1 domain.
PPAR-γ1 is expressed in a variety of cell types, including
adipocytes, muscle, macrophages, osteoblasts, and osteoclasts, whereas PPAR-γ2 expression is restricted to adipocytes, including marrow adipocytes, and is essential for
differentiation and maintenance of their phenotype and
function [9, 10]. The transcriptional activity of PPAR-γ is
controlled by binding of lipophilic ligands to the ligand
binding pocket. The natural ligands are derived from
nutrients or products of metabolic pathways and consist of
polyunsaturated fatty acid derivatives and ecosanoids [7].
Synthetic ligands include a class of antidiabetic drugs,
thiazolidinediones (TZDs), which bind to PPAR-γ with
high affinity, activate its adipogenic activity, and act as
insulin sensitizers [11].
PPAR-γ is essential for the regulation of energy storage.
The dietary abundance in fatty acids increases the activity of
PPAR-γ and leads to the activation of lipogenesis—a program
designed for energy storage in the form of accumulated lipids
in fat tissue. A scarcity of nutrients results in a decrease in
PPAR-γ activity and allows for lipolysis, a process that
mobilizes energy stored in a fat tissue. Continuous overnutrition leads to excessive upregulation of PPAR-γ activity,
increased lipid storage, and the development of obesity. In
addition, PPAR-γ plays an essential role in the regulation of
insulin signaling. Either deficiency or upregulation of PPARγ leads to the development of insulin resistance and
subsequently diabetes [12].
Perhaps not surprisingly, PPAR-γ also plays an important role in the maintenance of bone mass. The PPAR-γ2
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isoform regulates lineage commitment of MSCs toward
osteoblasts and adipocytes [4•]. As shown in a number of in
vitro models of MSC differentiation, as well as in primary
bone marrow cells, the activation of the PPAR-γ2 isoform
with natural (fatty acids and ecosanoids) or artificial (TZD)
ligands directs MSC differentiation toward the adipocyte
lineage at the expense of osteoblast formation [10].
Moreover, the activation of PPAR-γ2 in cells of the
osteoblast lineage converts them to terminally differentiated
adipocytes and irreversibly suppresses their phenotype,
including suppression of phenotype-specific genes [10,
13]. Thus, PPAR-γ2 acts as a positive regulator of
adipocyte differentiation and a dominant-negative regulator
of osteoblast differentiation. In contrast, the PPAR-γ1
isoform has been shown to promote both osteoclast
differentiation from a pool of hematopoietic stem cells
and bone resorption, by controlling the expression of c-fos
protein, an important determinant of osteoclast lineage
commitment and development [14].
Because both cellular components of bone remodeling
are under the control of PPAR-γ, the status of its activity is
important for maintaining the balance between bone
resorption and bone formation. Several animal models and
human studies have shown that changes in PPAR-γ
activity, which are determined by the level of protein
expression and the level of its activation, lead to unbalanced bone remodeling [14, 15, 16•, 17].
During the natural process of aging, bone mass declines
and fat mass in bone increases [18]. This correlates with
changes in the phenotype of MSCs (eg, the increased
expression of proadipocytic PPAR-γ2 and the decreased
expression of osteoblast-specific transcription factors,
Runx2 and Dlx5) [19]. Consequently, MSC differentiation
potential shifts toward adipogenesis and away from
osteoblastogenesis [19]. In addition, the availability of
oxidized derivatives of fatty acids, which are potent
activators of PPAR-γ, increases with aging [13, 20]. It
was also demonstrated that bone marrow derived from old
animals produces unknown PPAR-γ activator(s), which
stimulate adipocyte differentiation and suppress osteoblast
differentiation [19, 21].
The analysis of the gene expression profile in U-33/γ2
cells, a murine model of MSC differentiation under the
control of PPAR-γ2, showed that the presence of PPAR-γ2,
without activation by exogenous ligand, changes the
expression of a large number of genes involved in the
maintenance of MSC phenotype [22•]. Thus, with aging,
marrow-borne MSCs lose their “stemness” and are more
prone to adipocytic differentiation due to the increased
expression of PPAR-γ2 and the increased availability of
PPAR-γ activators. As a result, osteoblast number and bone
formation decrease while fat accumulation in bone
increases. In humans, the association between bone loss
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and increased marrow adiposity is visible not only during
aging, but also during conditions of skeletal disuse, such as
microgravity or paraplegia [23, 24]. In animals, skeletal
unloading results in bone loss, which is associated with
increased expression of PPAR-γ and an increase in the
marrow fat compartment [25, 26].
An essential role of PPAR-γ in the maintenance of bone
homeostasis was demonstrated in several animal models of
bone accrual or bone loss depending on the status of PPARγ activity [15, 16•, 17, 27–29]. In models of bone accrual, a
decrease in PPAR-γ activity in heterozygous PPAR-γ–
deficient mice or mice carrying a hypomorphic mutation in
the PPAR-γ gene locus led to increased bone mass due to
increased numbers of osteoblasts [17, 27]. Interestingly,
mice deficient in PPAR-γ expression in cells of the
hematopoietic lineage develop high bone mass and are
more resistant to the TZD-induced bone loss than control
mice [14]. In rodent models of bone loss due to PPAR-γ
activation, an administration of the TZD rosiglitazone
resulted in significant decreases in bone mineral density
(BMD), bone volume, and changes in bone microarchitecture [15, 16•, 28]. The observed bone loss was associated
with the expected changes in the structure and function of
bone marrow, which included decreased number of osteoblasts, increased number of adipocytes, and increased
production of receptor activator for nuclear factor-κB
ligand (RANKL), the cytokine physiologically responsible
for osteoclastogenesis.
The TZD-induced structure/function changes in the bone
marrow led to alterations in the ratio between the number of
osteoblasts and osteoclasts, suggesting an imbalance between bone resorption and bone formation. The degree of
bone loss in response to rosiglitazone treatment correlated
with age and the level of PPAR-γ expression in bone. In
younger animals with lower levels of PPAR-γ, bone loss
was less extensive than in older animals [16•]. Moreover,
age determines the mechanism by which bone loss occurs.
In younger animals, rosiglitazone administration decreased
bone formation, whereas in older animals it increased bone
resorption [16•]. Interestingly, in the absence of estrogen,
rosiglitazone enhanced bone loss, mainly due to increased
bone resorption pointing to the functional cross-talk
between PPAR-γ and estrogen receptor [29]. Such crosstalk has been recently described in osteoblasts as a form of
competition between PPAR-γ and the estrogen receptor for
a common coactivator, SRC-2 [30]. It would be interesting
to examine whether a similar mechanism is responsible for
the TZD-induced increase in bone resorption in a condition
of estrogen deficiency and during aging.
An analysis of gene expression in MSCs following
rosiglitazone treatment showed reduced expression of genes
essential for activity of signaling pathways controlling bone
homeostasis and MSC commitment to the osteoblast
Curr Osteoporos Rep (2010) 8:84–90
lineage, among them Wnt, transforming growth factor-β/
bone morphogenetic protein, and insulin-like growth factor1 [31•]. The effect of TZDs on the expression of genes
essential for osteoblast development was strikingly similar
to changes observed during aging. Due to the similarities
with age-related bone loss, some speculate that TZDs may
accelerate the aging of bone [16•, 19].
TZDs increase insulin sensitivity via activation of PPARγ. Two TZDs, rosiglitazone and pioglitazone, have been
used clinically since 1999. Despite TZDs’ beneficial
antihyperglycemic profile, their use is associated with
adverse effects on human bone [32]. Recently published
clinical evidence suggests that TZD therapy is associated
with a decrease in BMD and an increase in fracture risk.
The first evidence of increased fracture risk in TZD users
came from ADOPT (A Diabetes Outcome Progression
Trial), which compared the antihyperglycemic effects of
three different antidiabetic therapies with rosiglitazone,
metformin, or glyburide, for a median of 4.0 years in
randomly assigned individuals (1,840 women and 2,511
men) [33•]. Surprisingly, the effects were gender-specific,
and the fracture rates in men did not differ between
treatment groups and did not demonstrate a significant
difference in overall risk. The cumulative incidence of
fractures in women was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, and 7.7%
(3.7–11.7) with glyburide, representing hazard ratios of
1.81 and 2.13 for rosiglitazone compared with metformin
and glyburide, respectively. Fractures were seen predominantly in the lower and upper limbs; however, vertebral
fractures were not assessed. There was no correlation
between rosiglitazone use and estrogen status because both
premenopausal and postmenopausal women demonstrated
increase in fractures [33•]. Similarly, meta-analyses of data
from 10 randomized controlled trials showed that long-term
TZD use doubles the risk of fractures exclusively in woman
but not in men with type 2 diabetes mellitus [34•]. Finally,
the observational studies based on the United Kingdom
General Practice Research Database, which included a large
population of older individuals, concluded that TZD
therapy and its duration are associated with significant
increase in nonvertebral fractures independently of patient
age and sex. The adjusted odds ratio of fracture occurrence
for hip/femur was 4.54, for humerus was 2.12, and for
wrist/forearm was 2.90 [35].
PPAR-α
PPAR-α is expressed predominantly in the liver, and, to a
lesser extent, in muscle, in the heart, and in bone. In the
liver, it plays a crucial role in fatty acid oxidation, which
provides energy for peripheral tissues [36]. Mice deficient
Curr Osteoporos Rep (2010) 8:84–90
in PPAR-α are unable to meet energy demands during
fasting and suffer from hypoglycemia, hyperlipidemia, and
hypoketonemia. Conversely, PPAR-α activation with
fibrates, specific agonists, reduces adiposity, improves
hepatic and muscle steatosis, and improves insulin sensitivity [36]. PPAR-α regulates plasma lipid levels through
the control of fatty acid oxidation process. Fibrates are
wildly used in clinics to lower plasma triglyceride levels in
patients with hypertriglyceridemia [37].
PPAR-α is also expressed in bone, in cells of the
hematopoietic and mesenchymal lineages [38]. PPAR-α–
null animals do not exhibit an apparent bone phenotype
[39]. Bone mass is not altered and bone cortical area is not
different from control animals. In addition, the differentiation potential of the bone marrow toward osteoblasts and
adipocytes measured in ex vivo primary bone marrow
culture is not altered in PPAR-α–deficient mice [39].
However, PPAR-α deficiency has an effect on bone
morphology in male animals, which results in a significantly larger medullary space [39]. Although PPAR-α does
not regulate marrow mesenchymal cell differentiation, it
does regulate bone marrow myeloid cell commitment
toward the B cell lineage [40], implicating a role in the
bone marrow environment. In vitro studies demonstrated
that bezafibrates, which are PPAR-α and PPAR-δ agonists,
stimulate rodent osteoblast differentiation [41] and inhibit
human osteoclast development [42]. Moreover, in rats,
bezafibrates stimulated periosteal bone formation [41] and
increased femoral BMD while decreasing medullary area
[43]. Although these studies suggest anabolic effect of
bezafibrates on bone, therapeutic use of fibrates does not
appear to have an effect on the quality of human bone
because there is no change in the rate of fractures in
patients on fibrate therapy [44].
Thus, the available studies suggest that although PPARα does not play a critical role in differentiation of bone
cells, it may be important for bone metabolism by
providing energy through fatty acid oxidation and for the
regulation of the bone marrow milieu by regulating cell
commitment within hematopoietic lineages. Based on the
evidence that PPAR-α deficiency does not lead to changes
in the energy metabolism under normal conditions, it is
possible that the role of PPAR-α in bone is manifested in
challenging conditions such as high-fat diet or caloric
restriction. Both of these conditions lead to bone loss;
however, how these environmental challenges affect the
status of PPAR activity in bone is not known.
PPAR-δ
PPAR-δ, also called PPAR-β, is ubiquitously expressed in
many tissues including bone [38]. For years, the role of this
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nuclear receptor was obscure because of a lack of identified
selective agonists. Recently, animal models of genetically
altered PPAR-δ activity and availability of selective PPARδ agonists revealed a powerful role of this nuclear receptor
in fat-burning processes [45]. Transgenic expression of
PPAR-δ in adipose tissue produces mice that are resistant to
high-fat diet-induced obesity, hyperlipidemia, and tissue
steatosis. In contrast, mice deficient in PPAR-δ show
reduced energy uncoupling and are prone to obesity [46].
In skeletal muscle, PPAR-δ upregulates fatty acid oxidation
and energy expenditure to a far greater extent than PPAR-α
[45]. Taken together, PPAR-δ appears to perform a unique
function in the regulation of energy metabolism; it exceeds
the fatty acid oxidative activity of PPAR-α and, as a fat
burner, it opposes the fat-storing function of PPAR-γ.
The role of PPAR-δ in the regulation of bone homeostasis remains largely unknown. Although the bone status
in mice overexpressing or knocked down PPAR-δ was not
studied, one in vitro study suggests that PPAR-δ may
regulate bone resorption. The PPAR-δ selective agonist
L165041 dose dependently inhibited osteoclast differentiation in human peripheral blood mononuclear cell cultures,
but stimulated resorption, the activity of mature osteoclast,
as measured in an in vitro assay on dentine slices [42]. In
light of recent developments regarding the significance of
PPAR-δ for the regulation of energy metabolism and the
potential for the development of antiobesity therapies based
on selective activation of this nuclear receptor, more studies
are needed to assess the role of this regulator in fatty acid
metabolism in bone.
Bone Fat and Its Role in Local and Systemic Energy
Metabolism
All three PPARs are involved in adipocyte biology, either
by regulating adipocyte development and/or regulating
energy metabolism. The marrow adipocyte phenotype is
similar to that of adipocytes present in white and brown
fat, but the unique location of these cells in bone
presumably directs their more specialized functions
[47]. For years, marrow fat was merely considered a
cellular component of bone that served a passive role by
occupying space no longer needed for hematopoiesis.
However, recent developments suggesting that marrow fat
plays an essential role as an endocrine organ involved in
energy metabolism, places marrow fat under a new
research spotlight [47].
A relatively well-characterized role of marrow adipocytes is in the support of hematopoiesis by producing the
necessary cytokines and heat for hematopoietic cell
development [48]. In addition, marrow fat may participate
in lipid metabolism by clearing and storing circulating
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triglycerides thereby providing a localized energy reservoir
for emergency situations affecting, for example, osteogenesis (eg, bone fracture healing) [47]. Marrow adipocytes
produce a number of adipokines, but two of them (leptin
and adiponectin), whose expression is under PPAR-γ
control and which regulate caloric intake and insulin
sensitivity, are the focus of increased attention as possible
mediators of marrow fat endocrine function. Based on the
fact that cells of osteoblastic lineage express receptors for
leptin and adiponectin and the evidence that these adipokines may modulate osteoblast differentiation and function
[49, 50], it is reasonable to believe that bone fat has a local
endocrine function and that it modulates the marrow
environment supporting bone remodeling. Moreover, based
on the quantity of bone fat, which by the third decade of
human life occupies almost the entire cavity of long bones,
one can speculate that adipokines produced in bone may
enter the circulation and contribute to the systemic energy
metabolism. Thus, it is reasonable to propose that marrow
fat serves a number of endocrine functions not only of
local, but also systemic, significance. With advancing age,
fat cells infiltrate bone marrow cavities. It has even been
suggested that osteoporosis is an obesity-like disease of
bone [18]. Interestingly, with aging and other metabolic
diseases, a profile of cytokine expression changes in both,
in extramedullary fat depots and in bone [51, 52]. Thus, it is
possible that with aging, marrow fat undergoes changes
similar to visceral fat leading to the development of insulin
resistance and changes in insulin-dependent glucose and
fatty acid metabolism.
An analysis of the marrow fat response to TZDs presents
a paradigm that may unravel additional function(s) of
marrow fat. Microarray analysis of the PPAR-γ transcriptome in U-33/γ2 cells showed that rosiglitazone
significantly increased the expression of genes involved in
carbohydrate and fat metabolism, and inhibited the proinflammatory phenotype [31•]. Furthermore, the response of
marrow fat to TZDs is strikingly similar and distinctive
from that of extramedullary fat. There is a significant
upregulation of genes essential for fatty acid metabolism,
including fatty acid synthase, fatty acid-binding proteins,
hormone-sensitive lipase, uncoupling protein 2, and
cholesterol transporter CD36. Interestingly, although a
large number of genes involved in carbohydrate metabolism are upregulated, there is no change in the
expression of any of the important insulin-dependent
glucose transporters, including GLUT4. Most importantly, in marrow adipocytes, rosiglitazone induces the
expression of genes involved in insulin signaling, among
them the insulin receptor, insulin receptor substrate-1 and
FoxO1, while suppressing the expression of negative
regulators of this signaling network such as Socs3 [31•].
This profile suggests that upon rosiglitazone activation,
Curr Osteoporos Rep (2010) 8:84–90
marrow fat is sensitized to insulin and has increased fatty
acid metabolism.
Thus, marrow fat may acquire different physiologic
functions: 1) it may serve as an energy and heat provider; 2)
it may provide energy storage by accumulating an excess of
fat; 3) it may play a protective role and serve as a “sink” for
circulating triglycerides in pathologic conditions; and 4) it
may serve as an endocrine tissue sensitive to insulin.
Therefore, it is important to unravel the different functions
of marrow fat and to develop the means to manipulate this
tissue compartment for improving the outcome of therapies
for energy metabolism disorders.
Conclusions
Osteoporosis, obesity, and diabetes are the most common
pathologies occurring in highly industrialized countries
(US enters for Diseases Control and Prevention; http://
www.cdc.gov). Because PPARs are positioned at the
crossroads of the control of bone mass and energy
expenditure, the therapeutic manipulation of their activities may affect the skeleton, in both a positive and a
negative fashion. Conversely, pharmacologic harnessing
of the metabolic properties of marrow fat is an attractive
possibility for increasing our armamentarium to fight
metabolic disease.
Disclosure Dr. Beata Lecka-Czernik has received support from
funds from the US National Institutes of Health/National Institute on
Aging (NIA AG 028935) and American Diabetes Association’s
Amaranth Diabetes Fund 1-09-RA-95.
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