ORIGINAL ARTICLE
Role of Wnt Signaling in Bone Remodeling and Repair
Paul S. Issack, MD, PhD &David L. Helfet, MD & Joseph M. Lane, MD
Received: 16 November 2007/Accepted: 16 November 2007/ Published online: 8 December 2007
* Hospital for Special Surgery 2007
#
Hospital for Special Surgery 2007
Abstract The Wnt genes encode a highly conserved class
of signaling factors required for the development of several
types of tissues including musculoskeletal and neural
structures. There is increasing evidence that Wnt signaling
is critical for bone mass accrual, bone remodeling, and
fracture repair. Wnt proteins bind to cell-surface receptors
and activate signaling pathways which control nuclear gene
expression; this Wnt-regulated gene expression controls cell
growth and differentiation. Many of the components of the
Wnt pathway have recently been characterized, and specific
loss-of-function or gain-of-function mutations in this path-
way in mice and in humans have resulted in disorders of
deficient or excess bone formation, respectively. Pharmaco-
logically targeting components of the Wnt signaling
pathway will allow for the manipulation of bone formation
and remodeling and will have several orthopedic applica-
tions including enhancing bone formation in nonunion and
osteoporosis and restricting pathologic bone formation in
osteogenic tumors and heterotopic ossification.
The Wnt genes encode a highly conserved class of at least
19 secreted cysteine-rich signaling factors with multiple
roles during embryonic development, adult tissue repair,
and tumorigenesis [1–3]. They provide a paradigm of the
concept that cellular genes which are normally present
during embryogenesis and which regulate tissue develop-
ment are reactivated during tissue repair and can be
aberrantly activated in cancers [1, 4]. Wnt genes and their
signaling pathway play critical roles in cell fate determina-
tion, cell growth, and differentiation of several types of
tissues. [2] Recent studies of human orthopedic diseases
and specific mouse models suggest a clear role for Wnt
signaling in the regulation of bone formation, repair, and
remodeling [4–11]. Therefore, either enhancing or suppress-
ing Wnt signaling by manipulating components of the
signaling pathway may provide a potent therapeutic
approach to treating disorders of excessive or diminished
bone formation.
The Wnt signaling pathway
Wnt signaling proceeds through at least two distinct
pathways, a traditional or canonical pathway and a non-
canonical pathway. The canonical pathway signals through
β-catenin, while the non-canonical pathway uses different
mediators including G proteins [2, 12]. The vast majority of
published studies, including those on the roles of Wnt
signaling in osteogenesis, have examined the canonical
pathway, and that will be the focus of this review.
The canonical pathway is initiated byWnt ligands binding
to a complex receptor composed of members of the frizzled
gene family and low density lipoprotein receptor-related
proteins (LRP5 and LRP6; Fig. 1). The binding of Wnt
ligands to this receptor complex activates a signaling
pathway transduced by the cytoplasmic proteins glycogen
synthase kinase-3β (GSK-3), adenomatous polyposis coli
(APC), and β-catenin (Fig. 1). In the absence of Wnt
signaling, cytoplasmic levels of β-catenin are low because it
is phosphorylated by GSK-3. Phosphorylated β-catenin is
HSSJ (2008) 4: 66–70
DOI 10.1007/s11420-007-9072-1
P. S. Issack, MD, PhD (*)
Orthopaedic Trauma, Adult Reconstructive Surgery,
and Metabolic Bone Diseases,
Hospital for Special Surgery,
535 East 70th Street, New York, NY 10021, USA
e-mail: PSIssack@aol.com
D. L. Helfet, MD
Orthopaedic Trauma Service,
Hospital for Special Surgery and Weill-Cornell Medical Center,
New York, NY, USA
J. M. Lane, MD
Metabolic Bone Disease Service,
Hospital for Special Surgery, New York, NY, USA

targeted to a degradation pathway mediated by the APC
protein. In the presence of Wnt signaling, GSK-3 is
inactivated, thus, preventing phosphorylation of β-catenin.
Unphosphorylated β-catenin accumulates in the cytoplasm
and enters the nucleus where it associated with the T cell
factor (Tcf)/lymphoid enhancing factor (Lef) transcription
factors to regulate gene expression (Fig. 1)[1, 2, 4, 5].
There are several antagonists to the Wnt signaling pathway
(Fig. 1). Intracellular antagonists include GSK-3 and APC-3.
Extracellular antagonists include secreted frizzled-related
proteins (Sfrps) which contain the ligand binding domain of
frizzled but lack the transmembrane region [13, 14]. These
proteins can bind the Wnt ligands but cannot transduce the Wnt
signal, and thus, effectively block Wnt signaling. Dickkopf
(DKK) proteins are secreted factors which interfere with Wnt
signaling by binding to the LRP-5 and LRP-6 receptors [13, 15].
The latter two antagonists, Sfrps and DKK, are specific
antagonists of the canonical Wnt signaling pathway and are
proteins which may be commercially produced and used to
block Wnt signaling. GSK-3 and APC, in contrast, have more
global roles in cellular function and are thus less likely to be
targeted for specific blockage of Wnt signaling.
Wnt signaling in development and disease
Wnt genes were initially identified as genes potentially
responsible for mouse mammary tumor virus-induced
carcinogenesis in mice [3]. They were subsequently noted
to be present in several different species and important for
the development of several different types of tissues
including limbs and midbrain [1, 2]. Accumulating evi-
dence suggests that Wnt signaling is highly regulated
spatially and temporally. Specific Wnt genes are expressed
at very precise times and locations; aberrant expression of
Wnt signaling in the wrong tissue or at the wrong time in
development can result in cancers [16].
Several human diseases have been linked to abnormalWnt
signaling. Mutations in APC, which impair its ability to
degrade β-catenin, or mutations in β-catenin itself which
stabilize β-catenin, both result in constitutively active Wnt
signaling and have been linked to familial adenomatous
polyposis and colon cancer [16, 17]. Increased Wnt signaling
has been observed in several other cancers including
osteosarcomas and Ewing’s sarcoma [18, 19]. Mutations
which impair Wnt signaling have been linked to the rare
human disorder tetra-amelia marked by the absence of all
four limbs and craniofacial abnormalities [20].
A specific role for Wnt signaling in bone formation was
revealed by naturally occurring human mutations in the Wnt
signaling pathway. Loss-of-function mutations in the Wnt co-
receptor LRP5, which essentially blocks the canonical path-
way, results in osteoporosis pseudoglioma syndrome [21]
characterized by a low bone mass, an increased incidence of
fragility fractures, and visual defects (Fig. 2a–e). In contrast,
gain-of-function mutations in LRP5, which prevent inhibition
Fig. 1. The canonical Wnt signaling pathway. Wnt proteins bind to a
receptor complex composed ofmembers of the frizzled gene family (Fzd)
and low-density lipoprotein (LDL) receptor-related proteins (LRP).
Receptor binding inhibits glycogen synthase kinase-3β (GSK-3). In the
absence of Wnt signaling, GSK-3 phosphorylates β-catenin and targets
it to a degradation pathway mediated by the APC protein (APC). In the
presence of Wnt signaling, β-catenin escapes phosphorylation and
degradation and accumulates in the cytoplasm. Excess β-catenin enters
the nucleus where it associates with the lymphoid enhancing factor
(Lef)/T cell factor (Tc f) transcription factors to regulate gene expression.
Secreted frizzled-related proteins (Sfrps) contain the ligand binding
domain of frizzled but lack the transmembrane region; they can bind the
Wnt ligands but cannot transduce the Wnt signal, and thus, effectively
block Wnt signaling. Dickkopf (DKK) proteins are secreted factors
which also block Wnt signaling by binding to the LRP receptors
HSSJ (2008) 4: 66–70 67