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review article
mechanisms of disease
control of normal
bone remodeling
Osteoblasts
The adult skeleton continually turns over and re-
models itself through the coordinated activity of os-
teoclasts and osteoblasts on trabecular surfaces and
B
the haversian system. In normal bone, there is a bal-
anced remodeling sequence: first, osteoclasts re-
sorb bone, and then osteoblasts form bone at the
same site.
osteoclasts
Osteoclasts arise from precursor cells in the mono-
cytemacrophage lineage12 that differentiate into
inactive osteoclasts. Activated osteoclasts resorb
bone and eventually undergo apoptosis. As shown
in Figure 2A, both locally produced cytokines and
systemic hormones regulate the formation and ac-
C tivity of osteoclasts. The bone microenvironment
plays a critical role in the formation of osteoclasts
through the production of macrophage colony-
stimulating factor and receptor activator of nuclear
factor-kB (RANK) ligand (RANKL)13,14 by stromal
cells or osteoblasts.
RANKL, a member of the family of tumor necro-
sis factors, is expressed on the surface of osteo-
blasts and stromal cells and is released by activated
T cells.13 Most osteotropic factors, such as parathy-
roid hormone, 1,25-dihydroxyvitamin D3, and pros-
taglandins, induce the formation of osteoclasts by
increasing the expression of RANKL on marrow
Figure 1. Osteoclasts and Osteoblasts in Normal Bone
and Bone Metastasis. stromal cells and osteoblasts rather than by act-
Panel A shows osteoclasts and osteoblasts in normal ing directly on osteoclast precursors15,16 (Fig. 3).
bone (toluidine blue, 100). The large osteoclast is ac- RANKL binds the RANK receptor on osteoclast pre-
tively resorbing bone. Osteoblasts are small, cuboid cells cursors and induces the formation of osteoclasts by
that actively lay down bone matrix. Panel B shows osteo- signaling through the nuclear factor-kB and Jun
lytic bone metastasis (hematoxylin and eosin, 200). Re-
N-terminal kinase pathways. A soluble form of
nal carcinoma cells are invading the bone marrow, and
osteoclasts (arrows) are actively resorbing bone adjacent RANKL produced by activated T cells has been de-
to the tumor cells. Panel C shows osteoblastic metastasis tected in the joint fluid of animals with adjuvant ar-
(hematoxylin and eosin, 200). Thickened trabeculae and thritis.17
large numbers of osteoblasts are next to the bone sur- The importance of RANKL in the formation of
face, and there are tumor cells from adenocarcinoma of
osteoclasts has been demonstrated clearly by the
the lung between the two large trabeculae. Panel A was
provided by Dr. Hua Zhang, Helen Hayes Hospital, New technique of homologous recombination in which
York, and Panels B and C were provided by Dr. Brendan the RANKL or RANK gene has been deleted in mice
Boyce, University of Rochester, Rochester, New York. (knockout mice). These animals lack osteoclasts,
and as a result, severe osteopetrosis develops.18,19
osteolytic metastasis
In osteolytic metastases, the destruction of bone is
mediated by osteoclasts rather than tumor cells.32,33
However, the factors responsible for the activation
of osteoclasts vary depending on the tumor. In mul-
tiple myeloma, osteoclasts accumulate only at bone-
resorbing surfaces adjacent to myeloma cells; their
levels are not increased in areas uninvolved with tu-
Figure 3. Receptor Activator of Nuclear Factor-kB Ligand (RANKL)
and Osteoclast Formation.
mor.34 In addition to the increase in bone resorp-
RANKL is a potent inducer of osteoclast formation. Osteotropic factors, 1,25-
tion, bone formation is suppressed so that bone
dihydroxyvitamin D3, parathyroid hormone (PTH), prostaglandin E-2, and inter- lesions in patients with myeloma become purely
leukin-1, induce the formation of osteoclasts by up-regulating the expression lytic.35
of RANKL on the surface of marrow stromal cells and immature osteoblasts. Several osteoclastogenic factors have been impli-
RANKL then binds its receptor, RANK, on the surface of osteoclast precursors cated in the increased activity of osteoclasts in my-
and signals through the nuclear factor-kB (NF-kB)and Jun N-terminal kinase eloma.36 The leading candidates are interleukin-1,
(JNK) pathways to induce the formation of osteoclasts and promote osteo- interleukin-6, macrophage inflammatory protein
clast survival. In addition to RANK, a decoy receptor, osteoprotegerin, inhibits
1a, and RANKL. Interleukin-1 is a potent stimulant
RANKL binding to RANK. RANKL can also occur in a soluble form produced
of osteoclast formation,37 but levels of interleukin-1
by T cells in inflammatory states. The ratio of RANKL to osteoprotegerin de-
termines the level of osteoclastogenesis. produced by myeloma cells are extremely low.38 Sati
et al.39 and Soutar et al.40 did not detect signifi-
cantly increased levels of interleukin-1b in myelo-
ma samples, suggesting that interleukin-1 may not
fect the adherence of osteoclasts to bone or inhibit be a major mediator of myeloma bone disease.
proteases produced by osteoclasts, such as cathep- Interleukin-6 is a growth factor or at least blocks
sin K, are under development and may be useful for apoptosis of myeloma cells.41 It is present in mar-
treating bone metastases. row plasma samples from patients with myeloma.42
Interleukin-6 is a potent stimulator of osteoclast
osteoblasts formation43 and can enhance the effects of para-
Osteoblasts are the bone-forming cells. They arise thyroid hormonerelated peptide on the formation
from mesenchymal stem cells, which form osteo- of osteoclasts in vivo.44 Interleukin-6 levels in the
blasts, adipocytes, and muscle cells.25 A transcrip- marrow have not consistently been correlated with
tion factor that is critical for the differentiation of the presence of bone lesions, however.45,46 When
osteoblasts is Runx-2, or core-binding factor a1 myeloma cells adhere to marrow stromal cells, the
(CBFA1). CBFA1 drives the expression of most production of interleukin-6 by marrow stromal cells
genes associated with osteoblast differentiation.26 increases.47 Thus, interleukin-6 appears to have an
Bone does not develop in mice that lack the CBFA1 important role in enhancing the growth or prolong-
gene.27,28 The differentiation of osteoblasts is less ing the survival of myeloma cells, but its role in my-
well understood than the differentiation of osteo- eloma bone disease remains to be determined.
clasts. It is clear that there is an early osteoblast RANKL is a major mediator of myeloma bone
precursor that produces alkaline phosphatase and disease. Several studies have suggested that myelo-
a more differentiated precursor that produces in- ma cells produce RANKL,48,49 but it is unclear
creasing amounts of osteocalcin and calcified ma- whether the amount of RANKL produced by my-
trix.29 Osteoblasts eventually become osteocytes. eloma cells is sufficient to induce the formation of
Bone morphometric proteins are critical factors that osteoclasts. Instead, it may simply prevent apopto-
stimulate the growth and differentiation of osteo- sis of osteoclasts. RANKL is produced by marrow
of factors produced by the tumor cells themselves Supported by research funds from the Multiple Myeloma Re-
search Foundation; a Department of Veterans Affairs Merit Review
or by the microenvironment in response to the tu- Award; and grants (AR41336 and AG13625) from the National In-
mor that mediate the process of bone destruction. stitutes of Health.
These types of studies should result in the develop- I am indebted to members of the General Clinical Research Cen-
ter, University of Pittsburgh Medical Center, for their assistance in
ment of therapeutic agents to treat and possibly the care of my patients.
prevent this devastating complication of cancer.
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