Biomedical Engineering Reference
In-Depth Information
Equilibrium
RANKL
OPG
Osteoclast
Bone
Superiority of RANKL
OP
G
Bone
Osteoclast
Superiority of OPG
Osteoclast
Bone
Figure 1.28
Resorption activity of the osteoclast depends
on the ratio RANKL/OPG. OPG, osteoprotegerin; RANKL,
receptor activator of nuclear factor-
κ
B ligand. After [174].
to be related to the upregulation of the RANKL sheddase, TACE. The reduction
in transmembrane RANKL expression was preceded by a marked increase in the
expression of the metalloprotease disintegrin, TACE. Studies undertaken by Pan
et al
. indicate that ZOL, in addition to its direct effects on mature osteoclasts, may
inhibit the recruitment and differentiation of osteoclasts by cleavage of the trans-
membrane RANKL in osteoblast-like cells by upregulating the sheddase, TACE
[165, 187].
Wedemeyer
et al
. investigated the effect of a single subcutaneous dose of ZOL on
particle-induced osteolysis and observed excessive regional new bone formation.
They utilized the murine calvarial osteolysis model and polyethylene particles in
C57BL/J6 mice. Bone thickness was measured as an indicator of bone growth. Net
bone growth was significantly increased in animals with ZOL treatment [166, 188].
Proresorptive molecules that trigger bone loss (hormones and cytokines) induce
RANKL expression on osteoblasts. In the inflammatory conditions, activated T-cells
also produce RANKL. RANKL binding to RANK on mature osteoclasts and their
precursors activates a signal transduction cascade that leads to osteoclast formation
and activation. OPG protects bones because of binding to RANKL and inhibiting
osteoclastogenesis and osteoclast activation Figure 1.29.
Khosla remarks in his minireview that the identification of the OPG/RANKL/
RANK system as the dominant mediator of osteoclastogenesis represents a major
advance in bone biology. It ended a long-standing search for the specific factor
