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Introduction
Total joint replacement is a common operation performed
to treat severe arthritis affecting loading bearing joints for
its effectiveness in reducing pain and improving joint
function. However, wear particles resulting from the
degradation of joint arthroplasty components have significant
adverse influence on the survival of joint
arthroplasty[1]. Wear particles induced by osteolysis was considered one of
the principal contributors to implant aseptic loosening and
consequent joint revision operation after total joint
arthroplasty[2]. Wear debris stimulate peri-prosthetic inflammation,
activate phagocytic cells to secrete inflammatory cytokines
at a high level, such as interleukin (IL)-1, IL-6, and
TNF-α, which are osteoclastogenic, stimulate osteoblasts and
stromal cells expressing high levels of the receptor activator of
NF-κB ligand (RANKL), and decrease the ratio between
osteoprotegrin and RANKL[3_5]. Wear particles were
observed to cause adverse biological reactions which seem
to occur in the following order: inflammation, increased
osteoclastogenesis, and subsequent osteoclastic bone
resorption[6].
Increased osteoclastogenesis and activated osteoclast
function are known to be central to wear particles induced
by peri-prosthetic osteolysis and implant aseptic
loosening[7]. Cytokines, such as TNF-α and IL-1, play important roles in
wear particles induced by osteolysis according to
knowledge obtained from a mouse model of
osteolysis[8,9]. Because the increased osteoclastogenesis and osteoclast
activation is the center of wear particles induced by osteolysis,
inhibiting osteoclastogenesis and osteoclast function would
be important in treating or preventing aseptic loosening
after total joint replacement.
Tetracyclines and their non-antimicrobial,
chemically-modified analogues have properties that appear to modulate
host response by inhibiting the activity of the matrix
metalloproteinases that cause collagen destruction. They
also inhibit osteoclast function and stimulate osteoblastic
bone formation[10]. Doxycycline (DOX) belongs to
chemically-modified tetracycline antibiotics. Recently, it was
studied for its effect upon bone-related diseases. Previous
in vitro research showed that DOX was able to inhibit
in vitro osteoclastogenesis and cause apoptosis of mature
osteo-clasts; inhibiting osteoclasts caused bone
resorption[11,12]. These effects extend beyond the mere inhibition of matrix
metallo-proteinases (MMP).
In the present study, we utilized in
vitro culture of mouse bone marrow monocytes and rabbit mature osteoclasts to
study DOX on osteoclastogenesis and mature osteoclast
fate. We employed an in vivo mouse calvarial osteolysis
model to study whether DOX was able to inhibit wear
particles induced by inflammatory
osteolysis[13,14]. In doing so, we hoped to provide a foundation for advancing the use of
DOX in the treatment or prevention peri-prosthetic
osteolysis and aseptic loosening accruing after total joint
replace-ment.
Materials and methods
Inhibiting in vitro osteoclastogenesis with DOX
Osteoclasts were generated from osteoclast progenitors by
culture of primary mouse, non-adherent bone marrow
monocytes of 6_8-week-old male C57BL/J6 mice (Shanghai SLAC
Laboratory Animal Co, Shanghai,
China)[15]. Mouse bone marrow cells were collected from femoral and tibial shafts by
flushing with 8 mL cold αMEM (Gibco, Invitrogen, Grand
Island, NY, USA) containing 10% FCS (Hyclone, Tauranga,
New Zealand), 1% penicillin and streptomycin (Gibco,
Invitrogen, Grand Island, NY, USA). Cell suspensions were
passed through an 18 g needle in αMEM to disperse the
clumps. Bone marrow-adherent cells were removed by
incubating at 37 °C with 5% CO2 in a humidified incubator for
24 h in the 10 cm Falcon culture dish. The bone marrow
monocytes were isolated from the non-adherent cells in the
supernatant by using gradient centrifugal isolation in Ficoll
(The Second Chemical Reagent Factory of Shanghai, Shanghai, China). The bone marrow monocytes were then
cultured in the continuous presence of both macrophage
colony-stimulating factor (M-CSF, 30 ng/mL; Research
Diagnostics, Flanders, NJ, USA) and recombinant soluble
RANKL (100 ng/mL; Research Diagnostics, USA) for 7 d.
The culture medium was changed with fresh M-CSF and
RANKL every 48 h. DOX was added to the culture medium
at a final concentration of 5, 10, 15 or 20 µg/mL, respectively.
Seven days later, the cells were washed with
phosphate-buffer solution (PBS) and fixed in 2.5% glutaraldehyde for 5
min at room temperature. The commercial leukocyte acid
phosphatase kit was then used for tartrate-resistant acid
phosphatase (TRAP) staining (Shanghai Rainbow Medical
Reagent Research, Shanghai, China) and TRAP(+) cells were
counted[11,12].
Inhibiting mature osteoclast survival and function with
DOX Mature osteoclasts were isolated from 7 d old New
Zealand white rabbits (Shanghai SLAC Laboratory Animal,
China) as previously reported[16]. Briefly, after cervical
dislocation, the rabbits were sterilized in 75% ethanol for 5
min. Long bones were taken out and soft tissues attached to
bones were removed. The bones were minced in αMEM
containing 10% FCS plus 1% penicillin and streptomycin.
The cells were dissociated from the bone fragments by
vortexing for 30 s and the fragments were allowed to
sediment for 1 min. The cells in the supernatant were collected
and used as unfractionated bone cells.
5×106 bone marrow cells were seeded into 1 well of the 24-well plate and
incubated at 37 °C with 5% CO2 for 3 d. For the bone resorption
assay, 5×106 bone marrow cells were seeded onto 5×5 mm
bovine bone slices. DOX was added to the culture medium
at a final concentration of 5, 10, 15, or 20 µg/mL, respectively.
Three days later, the cells were washed with PBS and fixed in
2.5% glutaraldehyde for 5 min at room temperature. A
commercial leukocyte acid phosphatase kit (Shanghai Rainbow
Medical Reagent Research, China) was used for TRAP
staining. TRAP(+) cells with more than 3 nuclei were
counted [11,12]. After fixation, the cells on the bone slices
were washed off with 25% ammonium hydroxide and
sonicated 3 times for 5 min. The bone slices were then
dehydrated through an ethanol gradient and stained with 1%
toluidine blue and Mayer-hematoxylin. Positively stained
areas were counted as bone resorption pits and the
resorption area was calculated with Image Pro-Plus 5.0 (Media
Cybernetics, Bethesda, MD, USA).
Inhibiting wear particles induced by in
vivo osteolysis with DOX In accordance with the original model of wear
particulate induced by calvarial
osteolysis[14], polymethyl methacrylate (PMMA) or ultra-high molecular weight
polyethylene (UHMWPE) particles were applied to 8-week-old,
healthy C57BL/J6 male mice (Shanghai SLAC Laboratory
Animal Co, China) according to the official guidelines of the
Shanghai Jiaotong University School of Medicine (Shanghai,
China). The weight of the mice was 22±3 g. The animals
were randomly classified into 7 groups as follows with 6
mice in each group: (i) control group, where the mice
underwent sham operation; (ii) PMMA group, where the mice
received 30 mg PMMA particle implantation; (iii) PMMA+
2DOX group, where the mice received 30 mg PMMA particles plus 2 mg/kg DOX intraperitoneal injection every day
from d 1 to 7; (iv) PMMA+10DOX group, where the mice
received 30mg PMMA particles plus 10 mg/kg DOX
intraperitoneal injection every day from d 1 to 7; (v) UHMWPE
group, where the mice received 30 mg UHMWPE particle
implantation; (vi) UHMWPE+2DOX group, where the mice
received 30 mg UHMWPE particles plus 2 mg/kg DOX
intraperitoneal injection every day from d 1 to 7; and (vii) the
UHMWPE+10DOX group, where the mice received 30 mg UHMWPE particles plus 10 mg/kg DOX intraperitoneal
injection every day from d 1 to 7. The animals had free
access to water and food and were kept in 12 h on/12 h off
specific pathogen-free animal room.
The PMMA particles (provided by Dr Yong from
Technical Institute of Physics and Chemistry of China Academy of
Sciences, Beijing, China) were smaller than 10 µm. The
UHMWPE particles (a generous gift from Dr John,
University of Alabama, Birmingham, AL, USA) had a mean particle
diameter of 3.6 µm, with a range of 2.0_23 µm. The particles
were washed continuously in absolute ethanol for 48 h in a
shaker (Shanghai Centrifuge Institute, Shanghai, China) with
a speed of 200 r/min to remove adherent endotoxins
according to a previous report[17]. The particles were resuspended
in sterile PBS solution at a concentration of 300 mg/mL. The
particles' endotoxin level was lower than 0.1 EU/mL, as
determined using a commercial detection kit (Chromogenic
end-point TAL with a Diazo coupling kit (Xiamen Houshiji,
Fujian, China). The PMMA or UHMWPE particles were
stored at 4 °C before use.
The mice were anesthetized with 1% pentobarbital
sodium (Shanghai Chemical Reagent Co, Shanghai, China)
as an intraperitoneal injection at a dosage of 45 mg/kg. After
shaving, the skin was sterilized. An incision was made
between the tow external ears. As previously reported, a
1 cm middle sagittal incision was made, the subcutaneous
bursa was entered, and about a 1×1
cm2 area was exposed, with care not to disrupt the
periostrium[14]. 30 mg PMMA or UHMWPE particles in 100 µL sterile PBS was uniformly
spread over the exposed periostrium. The skin was closed
with simple disrupted suture to prevent leakage of the
particles. In the control group, the animals underwent
operation and 100 µL sterile PBS without particles. After the
operation, the mice were warmed up, recovered, and sent
back to the animal room.
Seven days later, the mice were killed with an overdose
of anesthesia and the calvariae were removed with care not
to split the sagittal suture. The specimens were freed off
soft tissue and the underlying brain was fixed in 4%
neutralized paraformaldehyde for 12 h and decalcified in 12.5% EDTA
(pH 7.4) at 4 °C for 2 weeks. The decalcification solution was
changed every 3 d. Then the specimens were treated in
graded ethanol for dehydration and embedded in paraffin.
Every specimen was sectioned with a 7 µm thickness on the
sagittal plane.
For the middle suture osteolysis area analysis, 5
consecutive sections of each specimen were stained with
hematoxylin-eosin (Shanghai Rainbow Medical Reagent Research,
China). Photos were taken at a magnification of 10× with use
of a Nikon Eclipse 80i microscope (Nikon, Tokyo, Japan)
attached to a computer. The middle suture was centered in
each image. The non-osseous tissue area adjacent and in
continuity with the midline suture was taken as the
osteolysis of the calvarial bone, traced by hand, and calculated with
Image Pro-Plus 5.0 (Media Cybernetics, USA).
For the osteoclastogenesis analysis, 5 consecutive
sections of each sample were stained using a commercial
leukocyte acid phosphate staining kit (Shanghai Rainbow
Medical Reagent Research, China). After removing the paraffin in
xylene, the sections were incubated in working solution for
90 min at 37 °C. After washing with water, the samples were
counterstained with 1% methyl green for 5 min at room
temperature. The sections were mounted in neutral balsam.
Red-stained cells in the middle suture and adjacent
non-osseous osteolsysis area were counted as TRAP(+)
osteo-clasts.
Statistical analysis All results were expressed as
mean±SD. The results were analyzed by ANOVA, followed
by Student's t-test to determine significance.
P<0.05 was considered significant.
Results
DOX suppressed osteoclastogenesis in
vitro Bone
marrow osteoclast precursors were induced into mature
osteoclast with RANKL and M-CSF added into the culture
medium. Many TRAP(+), multinucleated cells (with more
than 3 nuclei) formed compared to the control. No RANKL
and M-CSF were added into the culture medium (Figure 1).
In the osteoclastogenic medium, approximately 94.6±16.8
TRAP(+) osteoclasts formed 7 d later. There were no
TRAP(+) cells in the control wells. While DOX, applied at a
concentration of 5 µg/mL, significantly inhibited osteoclastogenesis
induced by RANKL and M-CSF, it completely abolished
osteoclast formation at the concentration of 20 µg/mL
(P<0.001; Figures 1 and 2A).
DOX influenced the survive of mature osteoclasts
in vitro After 3 d culture of unfractionated, newborn rabbit
marrow cell, TRAP staining showed that DOX strongly
influenced the survival of mature osteoclasts. However, we
did not observe a concentration gradient inhibition
phenomenon as previously reported[11]. At a concentration of 5
µg/mL, DOX treatment reduced the survival rate of mature
osteoclasts to approximately 50% compared with the control
levels, and the effect was significant (P<0.001; Figure 2B).
DOX at high concentrations up to 20 µg/mL did not increase
the inhibition effect.
DOX suppressed mature osteoclast bone
resorption After culture in αMEM on bovine cortical bone slices for 3
days, the bone resorption pits were counted and the
resorption area was measured. Osteoclast degraded bone matrix
and bone resorption appeared as the formation of many
resorption lacunae after staining with toluidine blue and
Mayer-hematoxylin (Figure 3C). The resorption pit number
was about 150.3±4.5 and the treatment of DOX, at a
concentration of 5 µg/mL, significantly reduced the resporption
lacunae number to 54.6±24.7 (P<0.001; Figure 3A). DOX at
high concentrations of up to 20 µg/mL further reduced the
number of resorption lacunae to 14±9
(P<0.001; Figure 3A). The resorption area measurement also showed that DOX
significantly reduced the resorption area on cortical slices
(P<0.001; Figure 3B). In the control, the resorption was
(34.7±4.8)×106
µm2. After adding DOX to the culture medium
with a final concentration of 5 µg/mL, the resorption area
was reduced to (9.2±4.4)×106
µm2. DOX, at high concentrations of up to 20 µg/mL, further reduced the resorption area
to (3.7±2.3)×106
µm2.
DOX inhibited in vivo osteolysis and osteoclastogenesis caused by wear particles
Sagittal suture resorption area No obvious resorption
was observed in the sagittal suture in group i (Figure 4). The
suture and adjacent non-osseous area increased in group c
and v in the animal receiving PMMA or UHMWPE particle
implantations (Figure 4). In the DOX-treated groups, bone
destruction and resorption were inhibited. The sagittal
suture resorption area in control group was 0.068±0.012
mm2. The sagittal suture resorption area in PMMA group was
0.335±0.130 mm2, significantly higher than that of the control
group (P<0.01; Figure 5A). In PMMA+2DOX group, the
mean sagittal suture area was 0.077±0.023
mm2, and in PMMA+10DOX group, the area was 0.079±0.029
mm2. PMMA+2DOX and PMMA+10DOX group had an obviously
smaller sagittal suture area than PMMA group
(P<0.001 and P<0.001; Figure 5A). In UHMWPE group, the resorption
area was 0.408±0.099 mm2 , much greater than that of the
control group (P<0.001). The suture area in group UHMWPE+
2DOX and UHMWPE+10DOX were 0.110±0.021
mm2 and
0.084±0.017 mm2, significantly smaller than that of UHMWPE
group (P<0.001 and P<0.001). PMMA or UHMWPE
particles were seen to induce obvious inflammatory osteolysis.
Thus, DOX treatment effectively inhibited inflammatory
osteolysis induced by wear particles.
Osteoclast number The osteoclast number within the
experimental areas in control group was 6.2±1.4. In PMMA
group, the number rose to 19.3±5.9. In PMMA+2DOX group
the TRAP(+) number was 5.3±1.5, while in PMMA+10DOX
group it was 5.4±1.6. In UHMWPE group, the number was
26.1±5.1, while in UHMWPE+2DOX and UHMWPE+10DOX
group it was 6.5±1.9 and 6.6±1.8, respectively (Figure 5B).
There was a significant difference in the osteoclast number
between the control and PMMA or UHMWPE particle
implantation groups (P<0.001, P<0.001). DOX treatment
strongly suppressed osteoclasto-genesis induced by PMMA
(P<0.001and P<0.001) or UHMWPE
(P<0.001and P<0.001) particles.
Discussion
Total joint replacement is a major advance in the
treatment of end-stage arthritis affecting main load-bearing joints
due to its effectiveness in improving joint function and
alleviating disabling pain[18]. Aseptic loosening due to
peri-prosthetic loosening is the major cause affecting the
long-term result of total joint replacement and the major reason for
complex joint revision arthroplasty
operations[19,20]. Small wear particles resulting from implant components fretting
stimulate a cascade of adverse biological reactions and
osteolysis, which finally results in arthroplasty aseptic
loosening.
Osteoclast is the center and final pathway of wear
particles induced by inflammatory osteolysis. So inhibiting
osteoclastogenesis and inflammation is an important step in
treating wear particles induced by osteolysis. Many
efforts have been made to treat or prevent wear particle
osteolysis[6,13,21_26]. Until now, only etanercept, a
TNFα receptor antagonist and bisphosphonate, has been applied
in clinical situations after total joint
arthroplasty[26_28]. The results have been unsatisfactory and no treatment
consensus has been reached. A great deal remains to be done.
Tetracyclines and their chemically-modified analogues
can inhibit the activity of MMP, which are considered to be
central for the inhibition of bone
destruction[29]. Recently, DOX was found to have some effect beyond inhibiting MMP
activities; it can inhibit osteoclastogenesis, cause apoptosis
of mature osteoclast, and inhibit the mature osteoclast bone
resorption function[11,12]. Previous
in vitro research has shown that DOX was able to inhibit peri-prosthetic interface
cells caused bone resorption through the inhibition the
activity of MMP in in vitro mouse calvarial organ culture
system[30]. However, the relationship between bone
destruction and MMP activity inhibition was not investigated. In
this in vitro mouse calvarial organ culture system, osteolysis
was attributed to increased osteoclastic bone
resorption[7].
In the present work, we used in vitro and in vivo
experiments to show that DOX can inhibit wear particles induced
osteoclastogenesis and osteolysis.
When culturing mouse bone marrow monocytes with the
stimulation of RANKL and M-CSF in vitro, many TRAP(+),
multinuclear osteoclasts formed[15]. DOX effectively
inhibited RANKL and M-CSF induced by osteoclastogenesis and
reduced TRAP(+), multinuclear osteoclasts. High
concentrations not only abolishes TRAP(+) osteoclast formation,
but inhibited TRAP(+) mono-nuclear cell formation. This
evidence strongly supports the conclusion that DOX can
effectively inhibit osteoclastogenesis. This is important for
treating wear particles induced by osteolysis with DOX, given
that increased osgteoclastogenesis is central to particle
inflammation reaction, as cytokines released by
macrophages can support the survival and activate the function of
mature osteoclasts[31,32]. So reducing the survival and
inhibiting the function of mature osteoclasts can also inhibit wear
particles induced by osteolysis.
Mature osteoclasts were isolated from newborn rabbits.
After culturing unfractionated bone marrow cells for 3 d
in vitro, TRAP staining showed that there were many mature
osteoclasts. DOX affected the fate of the mature osteoclasts.
After adding DOX to the culture medium, the number of
TRAP(+), multinuclear cells decreased significantly.
Seeding unfractionated newborn rabbit bone marrow cells on
bovine cortical bone slices, many resorption pits formed as
shown by toluidine blue-Mayer hematoxylin staining. The
resorption lacuna was big and deeply stained. DOX
significantly inhibited mature osteoclasts caused by bone
resorp-tion. It also reduced the number of resorption pits and the
total resorption area.
In vitro results confirmed that DOX treatment not only
decreased osteoclastogenesis, but also reduced the fate of
mature osteoclasts and their function. This was consistent
with previous reports[11,12]. However, the observed effect on
mature osteoclasts' fate was not according to previous
reports; we did not observe concentration gradient
inhibition phenomena.
In vivo wear particles induced mouse calvarial osteolysis
model is convenient for studying the mechanism of wear
particles induced by osteolysis and for studying the effect
of drugs aimed at interfering this
process[13,14]. When PMMA or UHMWPE particles were implanted in the calvariae of
C57/BL6 mice, they caused significant middle suture bone
resorption and inflammatory reactions as previously reported.
The middle suture and adjacent non-osseous osteolysis area
increased and the TRAP(+) osteoclast number increased.
Middle suture pathology analysis results showed that DOX
treatment protected calvarial bones from wear particles
induced by inflammatory osteolysis. For the first time,
in vivo data showed that DOX can effectively inhibit this
process.
The calvarium is a flat bone and no prosthesis is present;
it can not truly reflect the relationship of a prosthesis and
medullar canal. Therefore, in future studies, large animals
with a true prosthesis in the medullary canal are needed to
evaluate the effect of DOX in treating wear particles induced
by osteolysis. Further work must still be done to evaluate
the long-time toxic effect of DOX, because treating wear
particles induced by osteolysis and aseptic loosening needs
requires long-term use of medication. Although there are
shortcomings of the mouse calvarial osteolysis model,
it remains an inexpensive and convenient model for studying
the mechanism of wear particles induced by osteolysis and
for evaluating drugs aimed at intervening in this process.
In conclusion, DOX has been shown to effectively
inhibit wear particles induced by osteolysis via the
inhibition of osteoclastogenesis and the reduction of mature
osteoclast survival and function. The findings of the present
study suggest that DOX might successfully applied in the
treatment of osteolysis and aseptic loosening occurring
after total joint arthroplasty.
Acknowledgements
We would like to thank Dr Yong HUANG from the
Technical Institute of Physics and Chemistry of the China
Academy of Sciences (Beijing, China) and Dr John CUCKLER,
from the University of Alabama, for providing us with PMMA
and UHMWPE particles. We also thanked Dr Qi-ming FANG
for his kind help for the animal operations, and Ms Xi-feng
DONG for her kind help for the pathology processing.
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