REVIEW ARTICLE
Neuropeptide Y and osteoblast differentiation – the
balance between the neuro-osteogenic network and local
control
Filipa Franquinho
1,2,
*, Ma
´
rcia A. Liz
1,
*, Ana F. Nunes
3
, Estrela Neto
4,5
, Meriem Lamghari
4
and
Mo
´
nica M. Sousa
1
1 Nerve Regeneration Group, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal
2 Departamento de Anatomia Patolo
´
gica, Instituto Polite
´
cnico de Sau
´
de-Norte, Paredes, Portugal
3 iMed.UL, Faculty of Pharmacy, University of Lisbon, Portugal
4 INEB – Instituto de Engenharia Biome

Fax: +351 22 6099157
Tel: +351 22 6074900
E-mail: [email protected]
Website: http://www.ibmc.up.pt/nerve
*These authors contributed equally to this
work
(Received 29 March 2010, revised 2 June
2010, accepted 12 July 2010)
doi:10.1111/j.1742-4658.2010.07774.x
Accumulating evidence has contributed to a novel view in bone biology:
bone remodeling, specifically osteoblast differentiation, is under the tight
control of the central and peripheral nervous systems. Among other players
in this neuro-osteogenic network, the neuropeptide Y (NPY) system has
attracted particular attention. At the central nervous system level, NPY
exerts its function in bone homeostasis through the hypothalamic Y2 recep-
tor. Locally in the bone, NPY action is mediated by its Y1 receptor.
Besides the presence of Y1, a complex network exists locally: not only there
is input of the peripheral nervous system, as the bone is directly innervated
by NPY-containing fibers, but there is also input from non-neuronal cells,
including bone cells capable of NPY expression. The interaction of these
distinct players to achieve a multilevel control system of bone homeostasis
is still under debate. In this review, we will integrate the current knowledge
on the impact of the NPY system in bone biology, and discuss the mecha-
nisms through which the balance between central and the peripheral NPY
action might be achieved.
Abbreviations
CGRP, calcitonin gene-related peptide; ICV, intracerebroventricular; NPY, neuropeptide Y; PAM, peptidylglycine a-amidating monooxygenase;
SP, substance P; TTR, transthyretin; VIP, vasoactive intestinal peptide; WT, wild-type.
3664 FEBS Journal 277 (2010) 3664–3674 ª 2010 The Authors Journal compilation ª 2010 FEBS
However, as we will discuss throughout this review,

In relation to neural control of bone development,
most of the reports addressing this issue are based on
studies of bone innervation at different stages of
embryogenesis. During development, autonomic fibers
immunoreactive to protein gene product 9.5 and
ubiquitin C-terminal hydrolase (specific markers for
neural and neuroendocrine tissues) were found in rat
long bones at embryonic day 15, in the diaphyseal and
metaphyseal perichondrium, and became more fre-
quent after birth [15]. These observations were con-
firmed in later studies [16,17]. A detailed analysis of
bone innervation during development was also
provided [16]. In this study, sensory fiber-associated
neuropeptides, calcitonin gene-related peptide (CGRP)
and substance P (SP) were first observed at embryonic
day 21 in the epiphyseal perichondrium, the perios-
teum of the shaft, and the bone marrow. With regard
to NPY nerve fibers, their presence at postnatal day 4
was shown in diaphyseal regions, and at postnatal
days 6–8, these fibers were able to extend into the
metaphyseal region [15]. In developing calvaria, nerve
fibers were observed traversing the bone through the
periosteum, diploe, endosteum, dura, arachnoid and
pia at multiple locations with no particular pattern
[18].
In adult bones, sensory fibers derived from primary
afferent neurons present in the dorsal root and some
cranial nerve ganglia represent the majority of the skel-
etal innervation system, whereas the other nerve fiber
populations are adrenergic and cholinergic in nature,

acts on the brain to reduce food intake, by regulating
the activity of neurons in the hypothalamic arcuate
nucleus. To exert its function in this brain region,
leptin stimulates neurons that express anorexigenic
peptides, and inhibits neurons that coexpress the orexi-
genic peptides NPY and agouti-related protein [26].
Initially, the existence of multiple metabolic abnormali-
ties in ob⁄ ob mice made it experimentally challenging
to determine the mechanism by which leptin deficiency
led to increased bone mass [27–29]. As there are no
leptin receptors detectable on mouse osteoblasts [30]
F. Franquinho et al. NPY and osteoblast differentiation
FEBS Journal 277 (2010) 3664–3674 ª 2010 The Authors Journal compilation ª 2010 FEBS 3665
(ruling out the possibility of an autocrine, paracrine or
endocrine mechanism of regulation in the ob ⁄ ob
model), and given that the majority of leptin receptors
exist in the arcuate nucleus of the hypothalamus, the
hypothesis that leptin controls bone formation via a
central mechanism was raised. The most convincing
evidence supporting this hypothesis was the rescue
of the bone mass phenotype of the ob ⁄ ob mice by
intracerebroventricular (ICV) infusion of leptin in the
hypothalamic region, clearly demonstrating that the
inhibitory action of leptin on bone formation is medi-
ated by a central circuit [25]. Further supporting the
importance of leptin in the control of bone formation,
mice lacking the leptin receptor (db ⁄ db mice), similarly
to ob ⁄ ob mice, showed a three-fold increase in trabecu-
lar bone volume, owing to increased osteoblast activity
[25] (Table 1).

distinct from the pathway mediated by leptin [36].
The presence of nerve fibers immunoreactive to
NPY in the bone, mostly distributed alongside blood
vessels, was demonstrated in early studies [22,37].
Moreover, this NPY immunoreactivity was dramati-
cally reduced in sympathectomized animals, indicating
the sympathetic origin of these nerve endings [22].
Given the distribution of the NPY-positive nerve
fibers, it was initially proposed that this neuropeptide
had a vasoregulatory role in the bone, rather than
being a regulator of bone cell activity [15,38–40]. The
fact that NPY was produced by megakaryocytes and
mononuclear hematopoietic cells within the bone mar-
row supported this vasoregulatory role [41,42]. How-
ever, NPY-immunoreactive fibers were also identified
in the periosteum and cortical bone [41,43], raising the
possibility that NPY could play a role in bone biology
Table 1. Summary of the bone phenotype in animal models for leptin and for the NPY system. CBV, cortical bone volume; ND, not deter-
mined; TBV, trabecular bone volume.
Animal
model Deficiency Bone phenotype
Osteoblast
activity
Osteoclast
activity Other observations References
ob ⁄ ob Leptin Increased TBV
Decreased CBV
Increased in
trabecular bone
Increased Increased NPY levels 25,46

Y4 and Y2 Increased TBV in relation to Y2
) ⁄ )
Increased Increased Increased NPY levels 65
NPY
) ⁄ )
NPY Increased TVB and CBV Increased Normal ND 66
TTR
) ⁄ )
Transthyretin Increased bone mineral
density and TBV
Increased Normal Increased amidated
NPY Leptin
levels not altered
50
NPY and osteoblast differentiation F. Franquinho et al.
3666 FEBS Journal 277 (2010) 3664–3674 ª 2010 The Authors Journal compilation ª 2010 FEBS
besides the putative vasoregulation. Previous studies
had already demonstrated that osteoblasts are sensitive
to treatment with NPY [44,45], suggesting the presence
of NPY receptors in bone cells and raising the possibil-
ity that NPY might be directly involved in the regula-
tion of osteoblast activity. NPY is able to act through
five different receptors (Y1, Y2, Y4, Y5 and y6) that
vary in their binding profiles and in their distribution
in the central nervous system and periphery. Y1, Y2
and Y5 are the best characterized NPY receptors, and
the majority of NPY functions are associated with
them. Supporting the assumption that Y receptors are
present in bone cells, one of the NPY receptors, Y1,
was shown to be present in human osteoblastic and

that came from the analysis of these animal models
was that the actions of the NPY system in bone
biology are more complex than simple downstream
mediation of leptin. The studies that allowed these
conclusions are summarized and discussed below.
A definite role for the NPY receptors in the regulation
of bone turnover was demonstrated following germline
deletion of Y2 [51]. Y2
) ⁄ )
mice had a two-fold increased
bone volume, as indicated by the increased trabecular
bone volume and thickness (Table 1). This augmented
bone volume resulted from increased bone formation
i.e. from elevated osteoblast activity. Moreover, in vitro
analysis of Y2
) ⁄ )
mesenchymal stem cells revealed an
increased number of osteoprogenitor cells, which may
additionally underlie the increase in bone formation in
the absence of Y2 in vivo [46].
Whereas, in WT bone marrow stromal cells, Y1
expression is detected (and expression of Y2, Y4, Y5
or y6 is absent), in Y2
) ⁄ )
bone marrow stromal cells
the expression of all five known Y receptors is absent
[46]. Therefore, the effect observed in Y2
) ⁄ )
mice was
thought to be mediated by a centrally controlled mech-

NPY.
F. Franquinho et al. NPY and osteoblast differentiation
FEBS Journal 277 (2010) 3664–3674 ª 2010 The Authors Journal compilation ª 2010 FEBS 3667
in either germline or hypothalamus-specific Y2
) ⁄ )
mice
[51]. The rapid increase in bone mass in adult mice
after hypothalamic deletion of Y2 raises the prospect
of new possibilities in the prevention and treatment of
osteoporosis, a major concern following estrogen defi-
ciency after menopause. In this respect, it has been
shown that the elevated osteoblast activity that charac-
terizes the skeletal phenotype of Y2
) ⁄ )
mice is main-
tained following gonadectomy in both female and male
mice, and that the protection against gonadectomy-
induced bone loss is also evident following hypothala-
mus-specific deletion of Y2 in both male and female
mice [53]. Further supporting a link between estrogen
and NPY, it is known that estrogen deficiency tran-
siently increases NPY expression in the hypothalamus
[54], which could contribute to the bone loss associated
with this condition. The topic of NPY and sex hor-
mone interactions in bone and fat control has been
recently reviewed [55]. In summary, increased knowl-
edge about the link between NPY and sex hormones
in regulating bone biology could lead to better treat-
ments for osteoporosis.
Despite the initial consensus that Y2 is not

mass. Moreover, it led to the hypothesis that NPY
might be a common mediator underlying the high
bone mass in these two mouse models [40]. However,
on comparison of the long bones of male Y2
) ⁄ )
and
ob ⁄ ob mice, an opposite effect between cortical and
trabecular bone is observed under conditions of leptin
deficiency, whereas in Y2
) ⁄ )
mice, both cortical and
trabecular bone mass are increased [60]. These findings
suggest that the Y2 and leptin antiosteogenic path-
ways occur via distinct mechanisms, thereby showing
diversity in the hypothalamic control of bone homeo-
stasis.
To further investigate the consequences of the above
findings, the effect of Y2 depletion on bone cell activ-
ity was studied under conditions of elevated leptin and
NPY by overexpressing NPY in the hypothalamus of
Y2
) ⁄ )
mice [25]. These animals had a marked increase
in leptin levels, and thereby an increase in body weight
and adipose mass. As expected, this increase in NPY
and leptin levels led to a decrease in bone formation
[25]. This was observed when NPY was overexpressed
in both Y2
) ⁄ )
and WT mice. However, Y2

fibers, local NPY production in bone cells has been
reported recently [49,50]. This local production indi-
cates the possibility of an alternative pathway to the
central regulation of bone homeostasis. However,
the two independent in vitro studies showing local
NPY production in bone cells gave conflicting results
concerning the implications of NPY for osteoblast
differentiation. This discrepancy is probably related
to the different approaches used and the distinct
questions addressed. Igwe et al. [49,50] analyzed the
role of NPY in osteoblast differentiation with the use
NPY and osteoblast differentiation F. Franquinho et al.
3668 FEBS Journal 277 (2010) 3664–3674 ª 2010 The Authors Journal compilation ª 2010 FEBS
of mouse calvarial osteoblasts in the presence of
NPY, whereas Nunes et al. [49,50] used primary bone
marrow stromal cells isolated from transthyretin (TTR)
knockout mice (which display high levels of NPY in
the brain and bone), without NPY treatment. There-
fore, the direct effect of local NPY on bone cells
remains poorly understood and requires additional
analysis.
The in vitro actions of NPY on osteoblasts suggested
the existence of Y receptors in this cell type [37,43]. In
fact, Y1 was found to be already highly expressed in
bone marrow stromal cells and bone marrow osteopro-
genitor cells differentiating to the osteoblast lineage
[40,46–48,62]. Its expression is downregulated in Y2
) ⁄ )
mice, given the elevated NPY levels in these animals
[46]. This finding is consistent with in vitro studies

blasts, providing a likely mechanism for the high bone
mass phenotype of Y1
) ⁄ )
mice [63]. Additionally,
when targeted deletion of Y1 was performed in the
hypothalamus, bone density was not altered, further
supporting the specific role of Y1 in the local control
of bone remodeling [62].
As detailed above, the presence Y1 in osteoblasts
and other peripheral tissues suggests that, in addition
to a neural circuit, systemic factors may also interact
with Y1. It is therefore possible that these factors
converge on Y1 to modulate peripheral processes. To
test this possibility, the interaction of Y1 with several
known regulators of bone, including leptin, sex
steroids and NPY, was assessed in in vivo models [64].
This study demonstrated that androgens are required
for activation of the bone anabolic response in Y1
) ⁄ )
mice. Interestingly, an increased hypothalamic NPY
level was able to reduce osteoblast activity in WT and
Y1
) ⁄ )
mice, but Y1
) ⁄ )
mice retained higher osteoblast
activity. In consequence, it was suggested that other
signals (probably acting through androgens), and not
only changes in NPY activity, are needed for the
anabolic activity of Y1

of both osteoblast and osteoclast activity [62]. In view
of these findings, it was suggested that Y1 and Y2
might act at different points along a common signaling
pathway. In this respect, it has been recently shown
that NPY induces Y2 upregulation and Y1 downregu-
lation in osteoblasts, stimulating the differentiation of
bone marrow stromal cells [57]. Therefore, given the
complexity of the NPY–Y2–Y1 crosstalk, further
research is needed to explore in more detail the rela-
tionships among the signaling evoked by Y1 and Y2
and osteoblast activity. Also, several questions remain
to be answered concerning the direct action of NPY
on osteoblasts, as well as in relation to the mechanisms
underlying the regulation of bone homeostasis via Y2:
can the effects of Y2 be exclusively attributed to the
hypothalamus, or should a peripheral pathway be con-
sidered?
F. Franquinho et al. NPY and osteoblast differentiation
FEBS Journal 277 (2010) 3664–3674 ª 2010 The Authors Journal compilation ª 2010 FEBS 3669
Y4 – an additional player in bone
remodeling?
As described above, Y1 and Y2 have been clearly
linked to bone biology. No information existed, how-
ever, concerning the remaining Y receptors until germ-
line deletion of Y4 was produced [65]. Although bone
mass was unaltered in Y4
) ⁄ )
mice (Table 1), a syner-
gistic relationship in the regulation of bone metabolism
was described between the Y2 and Y4 pathways. Dele-

precisely. In this respect, the initial report on NPY
) ⁄ )
mice, by showing no changes in bone volume in this
animal model, raised important doubts concerning the
control of bone activity by this neuropeptide [66].
However, one should bear in mind that, although
NPY is their main ligand, the Y receptors can also be
activated by peptide YY and pancreatic polypeptide.
Consequently, it was hypothesized that this redun-
dancy may underlie the lack of a bone phenotype in
NPY
) ⁄ )
mice [67]. In contrast to the observations in
NPY
) ⁄ )
mice, the same group showed a significant
increase in bone mass following loss of arcuate nucleus
NPY-producing neurons [66]. To further substantiate
the role of NPY in the control of bone homeostasis, a
recent study employed several NPY mutant mouse
models including specific reintroduction of NPY into
the hypothalamus of adult NPY
) ⁄ )
mice [67]. In this
more recent study, and in contrast to what was previ-
ously reported, NPY
) ⁄ )
mice were described as having
significantly increased bone mass resulting from an
enhanced osteoblast activity (Table 1). This generalized

bone volume, although osteoblast activity, estimated
by osteoid width, was markedly reduced following
adeno-associated virus (AAV)–NPY injection [61,64].
However, with regard to this central NPY overexpres-
sion, the consequential increase in leptin levels [68,69],
was not excluded as the cause of the effects observed.
Besides delivery of NPY, the TTR knockout mouse
(TTR
) ⁄ )
) has been described as a model of increased
NPY, given the overexpression of peptidylglycine
a-amidating monooxygenase (PAM) [70], the rate-limit-
ing enzyme in the process of neuropeptide maturation
[71]. As NPY requires PAM-mediated a-amidation for
biological activity [72], PAM overexpression in TTR
) ⁄ )
mice results in increased levels of processed amidated
NPY, without an increase in NPY expression [50]. As
expected, this strain has increased NPY content in the
brain and bone, and this finding was related to
increased bone mineral density and trabecular volume,
arguing against the generalized antiosteogenic activity
of NPY. In agreement with these observations, TTR
) ⁄ )
bone marrow stromal cells had increased NPY levels
and exhibited enhanced competence in undergoing
osteoblastic differentiation. In the case of TTR
) ⁄ )
mice, one should, however, bear in mind that it is
possible that, as a consequence of PAM overexpression,

of knowledge has been derived from the analysis of
Y receptor knockout mice. Therefore, the majority of
the studies discussed in this review regarding the
involvement of NPY in bone metabolism have been
generated with mice as a model. The relevance of this
network in humans has not yet been addressed. There
is an urgent need to complement these studies with
clinical research, to further confirm their relevance and
to prepare for the future design of new therapeutic
strategies for bone disease ⁄ injury.
Y1 and Y2 have been shown to be independently
involved in the control of bone formation, whereas a
possible synergistic interaction between Y4 and Y2 has
been described. However, it remains to be established
whether other Y receptors are also involved in bone
remodeling. Moreover, the crosstalk between the dif-
ferent Y receptors in this process is still obscure. Addi-
tionally, the direct effect of local NPY on bone cells
remains controversial. What would be the effects of
direct NPY injection into the bone? What is the signifi-
cance and what are the consequences of local NPY
expression by different bone cell types? We should
now not only concentrate on understanding the impli-
cations of these novel findings, but also explore them
with new experimental designs to better understand
them.
In summary, the biology of the control of bone mass
by NPY still needs to be further explored, as not only
do several questions remain open, but also controversy
still exists: how is the balance between the neuro-osteo-

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