55.
Mechanically induced osteoclast differentiation is associated with
alterations in genes regulating IL-6 signaling, cell death and osteoblast
differentiation
Rune V. Madsen, Benjamin McArthur, Aleksey Dvorzhinskiy, F. Patrick Ross,
Mathias P. Bostrom, Anna Fahlgren
University of Copenhagen; , Hospital for Special Surgery, New York, USA; ,
Hospital for Special Surgery, New York, USA; , Hospital for Special Surgery,
New York, USA; , Hospital for Special Surgery, New York, USA; , Linköping
University, Linköping, Sweden
Background:
Mechanical loading of bone is anabolic, while aseptic loosening
of implants is catabolic. In a rat model of mechanically induced aseptic
loosening, osteoclast differentiation is increased dramatically, but the
mechanisms are unknown.
Purpose / Aim of Study:
The aim was to profile molecular pathways in peri-
implant bone resorption.
Materials and Methods:
We used 42 male rats in a validated model for
mechanically induced implant loosening. A titanium plate with a central screw
was inserted on the proximal tibia. These were allowed to osseointegrate for 5
weeks. Thereafter, the screw was replaced with a piston that moved
perpendicular to the bone surface/plate. We performed microarrays after 3, 6,
12, 24
and 36 hours on cortical bone samples exposed to pressurized fluid
flow, using time 0 as controls.
Findings / Results:
Of a total of 4093 genes that underwent a 1.25-fold
change (p<0.05) due to fluid flow, only 21 were common for all time points.
Signals linked to inflammation and apoptosis were regulated in a biphasic
manner at 3 and 12 and/or 24 hrs. The acute response at 3 hrs was associated
with increases in the cytokines IL-6, IL-11, LIF and STAT3. Levels of the pro-
apoptotic factor TWEAK were higher while those of BOK, a second pro-
survival molecule, were lower. There is an early and late rise in RIPK3, which
stimulates a form of programmed necrosis. Osteoblast-related genes were
clearly suppressed (osteocalcin, Col1a, PTHr1), while those regulating
macrophage and osteoclast differentiation (CSF-1, Bach1, HO-1, RANKL,
RANK, OPG) were enhanced.
Conclusions:
The data suggests that mechanical loading of cortical bone
stimulates time-dependent expression of genes regulating the survival, necrosis
and differentiation of both the myeloid and mesenchymal cell lineages,
resulting in an integrated response leading to a rapid increase in osteoclast
numbers.
