NEOPLASIA
Comment on Yaccoby et al, page 2106
Advances in myeloma therapy:
breaking the cycle
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Carl Gregory TULANE UNIVERSITY HEALTH SCIENCES CENTER
In this issue, Yaccoby and colleagues demonstrate that anti-
bodies directed against the canonical Wnt inhibitor Dickkopf-1
(DKK1) suppress tumor-induced bone resorption in a murine
model of multiple myeloma. This study represents the first
attempt to assess the feasibility of anti-DKK1 therapy for the
treatment of bone resorption in malignant bone diseases.
Multiplemyeloma(MM)isafatalmalig- contrastingdiseasesof
nancy involving the plasma cells of the
bone: one that results
blood. One of the hallmark characteristics as-
in a form of osteoporo-
sociated with the disease are osteolytic lesions
sis2 and the other, ab-
(OLs) that occur throughout the skeleton,
normally high bone
causing intractable bone pain and pathological
mass.3 Mutations that
fractures. It has been known for some time
cause complete loss of
that the formation of OLs occurs through hy-
function of LRP5 re-
peractivation of bone-resorbing osteoclasts
sult in a form of osteo-
through the action of cytokines that are se-
porosis. Conversely,
creted by the MM cells. The MM cells reside
abnormally high bone
and flourish within the nutrient- and cytokine-
mass can be caused by
Scheme depicting the proposed role of DKK1 in osteolytic lesion formation and
enriched cavities of the lesions, continuing the
mutations in LRP5
maintenance in multiple myeloma. msc indicates mesenchymal stem cell;
promotion of osteolysis and establishing a de-
localized to the DKK1
clast, osteoclast. Illustration by Paulette Dennis.
structive cycle that is the major cause of mor-
binding domain that
bidity associated with the disease (see the
prevents negative
figure).
regulation of the Wnt pathway.
Anti-DKK1 agents may therefore represent
For years, the treatment of OLs has fo-
Yaccoby and colleagues demonstrate here
the next generation of therapeutic options for
cused on the inhibition of osteoclastogenesis
that administration of DKK1-binding anti-
the enhancement of bone repair in some malig-
by administration of bisphosphonates, but
bodies prevents inhibition of osteogenesis in a
nant and degenerative bone diseases.
even when osteoclast activity is controlled, the
model of MM. This was demonstrated by co-
The author declares no competing financial
lesions never repair, suggesting that MM cells
implantation of rabbit bones and fresh human
interests.
disrupt the anabolic axis of bone formation
MM cells into immunocompromised mice.
too. Recently, Tian et al1 observed that secre-
After some time, the implants of control ani-
REFERENCES
tion of an inhibitor of the canonical wingless
mals showed signs of MM-induced resorp-
1. Tian E, Zhan F, Walker R, et al. The role of Wnt signaling
(Wnt) signaling pathway, DKK1, by MM
tion, whereas treatment of recipient mice with
antagonist Dkk-1 in the development of osteolytic lesions in
multiple myeloma. N Engl J Med. 2003;349:2483-2494.
cells strongly correlated with the severity of
anti-DKK1 antibodies blunted resorption and
2. Gong Y, Slee RB, Fukai N, et al. LDL receptor-related
osteolytic lesions. Given that signaling by the
improved the bone mineral density of the im-
protein 5 (LRP5) affects bone accrual and eye development.
canonical Wnt pathway is critical for the dif-
plants. As the authors of this article state, aber-
Cell. 2001;107:513-523.
ferentiation of progenitors into osteoblasts, it
rant regulation of Wnt signaling may affect
3. Boyden LM, Mao J, Belsky J, et al. High bone density
due to a mutation in LDL-receptor-related protein 5.
seemed clear that the bone repair deficit in
bone repair in other malignant diseases of the
N Engl J Med. 2002;346:1513-1521.
MM lies in the osteoinhibitory properties of
skeleton. Indeed, the osteoinhibitory proper-
4. Hall CL, Kang S, MacDougald OA, Keller ET. Role of
DKK1 (see figure). The best evidence for the
ties of DKK1 have been reported in an animal
Wnts in prostate cancer bone metastases. J Cell Biochem.
2006;97:661-672.
importance of Wnt signaling in osteogenesis is
model of prostate cancer,4 and abnormally
5. Gregory CA, Gunn WG, Reyes E, et al. How Wnt sig-
the finding that mutations in the gene that
high levels of DKK1 have been detected in the
naling affects bone repair by mesenchymal stem cells from
encodes the Wnt receptor, LRP5, can cause 2
serum of individuals with osteosarcoma.5
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1 MARCH 2007 I VOLUME 109, NUMBER 5 blood

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