Volume 22, Number 12, 2007
Published online on August 13, 2007; doi: 10.1359/JBMR.070802
© 2007 American Society for Bone and Mineral Research
Bone Regeneration Is Regulated by Wnt Signaling
Jae-Beom Kim,1,2 Philipp Leucht,1,2,3 Kentson Lam,1 Cynthia Luppen,1 Derk Ten Berge,4 Roel Nusse,4 and
Jill A Helms1
ABSTRACT: Tissue regeneration isincreasingly viewed as reactivation of a developmental process that, when
misappropriated, can lead to malignant growth. Therefore, understanding the molecular and cellular pathways that govern tissue regeneration provides a glimpse into normal development as well as insights into
pathological conditions such as cancer. Herein, we studied the role of Wnt signaling in skeletal tissue regeneration.Introduction: Some adult tissues have the ability to regenerate, and among these, bone is one of the most
remarkable. Bone exhibits a persistent, lifelong capacity to reform after injury, and continual bone regeneration is a prerequisite to maintaining bone mass and density. Even slight perturbations in bone regeneration can
have profound consequences, as exemplified by conditions such as osteoporosisand delayed skeletal repair.
Here, our goal was to determine the role of Wnts in adult bone regeneration.
Materials and Methods: Using TOPgal reporter mice, we found that damage to the skeleton instigated Wnt
reporter activity, specifically at the site of injury. We used a skeletal injury model to show that Wnt inhibition,
achieved through adenoviral expression of Dkk1 in the adult skeleton,prevented the differentiation of
Results: As a result, injury-induced bone regeneration was reduced by 84% compared with controls. Constitutive activation of the Wnt pathway resulting from a mutation in the Lrp5 Wnt co-receptor results in high
bone mass, but our experiments showed that this same point mutation caused a delay in bone regeneration.
In these transgenic mice,osteoprogenitor cells in the injury site were maintained in a proliferative state and
differentiation into osteoblasts was delayed.
Conclusions: When considered together, these data provide a framework for understanding the roles of Wnt
signaling in adult bone regeneration and suggest a feasible approach to treating clinical conditions where
enhanced bone formation is desired.
J Bone MinerRes 2007;22:1913–1923. Published online on August 13, 2007; doi: 10.1359/JBMR.070802
Key words: Dkk, Lrp5, osteoblast, differentiation, repair, regeneration
LTHOUGH HUMANS CANNOT grow new limbs like salamanders, the molecular machinery for regeneration
seems to be an elemental part of our genetic makeup. The
prevailing opinion in regenerative medicine is that the
genesresponsible for regeneration have for some reason
fallen into disuse and that they may be “jump-started” by
the selective activation of key molecular pathways. Here,
we study one such pathway regulated by Wnt proteins.
Wnt ligands are secreted molecules that bind to cell surface receptors encoded by the Frizzled and low-density lipoprotein receptor-related proteins (LRPs). Once bound,
theligands initiate a cascade of intracellular events that
eventually lead to the transcription of target genes through
The authors state that they have no conflicts of interest.
the nuclear activity of -catenin and the DNA binding protein TCF.(1–3) The majority of studies have focused on
-catenin–dependent (canonical) Wnt signaling, but accumulating evidence indicates that Wnts can alsoparticipate
in -catenin–independent processes. There remains only a
cursory understanding of how cells integrate and respond to
Wnts, especially in an in vivo setting, and it was in this
context that we initiated out study of the contribution of
Wnt signaling to adult bone repair.
Wnts are involved in a wide variety of cellular decisions
associated with the program of osteogenesis. For example,...