The influence of wear particles in the expression of osteoclastogenesis factors by osteoblasts

doi:10.1016/j.biomaterials.2004.01.053

Biomaterials

Volume 25, Issue 27, December 2004, Pages 5803-5808

https://doi.org/10.1016/j.biomaterials.2004.01.053 Get rights and content

Abstract

Orthopedic implant failures are often associated with peri-implant osteolysis. Particles generated from the wear process have been suspected to play an important role in this situation. Indeed, the peri-implant osteolysis could be due to the presence of particles stimulating the osteoclastogenesis process. We hypothesize then that the presence of a low particle concentration positively influences osteoblasts to produce osteoclastogenesis factors. If true, this hypothesis would then support the idea that the particles could be at the origin of the process leading to implant loosening. To check the validity of this hypothesis, we quantified in vitro the production of different genes involved in the osteoclastogenesis process using primary isolated human osteoblasts treated or not with particles. Results showed that low concentrations of particles might have a stimulating effect on osteoblasts to produce osteoclastogenesis factors as demonstrated by the increase of RANKL and CSF-1 gene expression in the particle group.

Introduction

Due to its mechanical design, an artificial joint is inevitably subjected to a wear process that generates particles. Depending on the materials used, large amount of particles can be created at the different interfaces of the implant [1]. These particles are in direct contact to the cells located in the peri-implant bone.

The presence of wear particles can activate an inflammatory cascade resulting in a bone resorption process [2], [3], [4]. This process can finally lead to the aseptic loosening of artificial joints, the major cause of implant failures [1], [5].

Recently, wear particles were also shown to have an adverse effect on bone formation [6], [7]. Titanium (Ti) particles downregulated the gene expression of type I collagen [8], while UHMWPE particles were shown to affect osteoblast differentiation [9]. We showed that particles had a cytotoxic effect [10], modulated the fibronectin gene expression [11], and decreased the adhesion strength [12] of osteoblasts. Moreover, combination of particles and cytokines had a synergic effect on the production of inflammatory factors [13]. Using microarray techniques, it has been shown that particles had a profound impact on genes coding for inflammatory cytokines and genes controlling the nuclear architecture [14]. Nevertheless, little information is available regarding the effect of particles on osteoclastogenetic factors produced by osteoblasts. Moreover, previous in vitro studies used relatively high concentrations of particles that could correspond to an already advanced situation in the loosening process of the implant [15].

The peri-implant osteolysis is a degenerating process that can start when low concentrations of particles are present. Over years of wear process, an accumulation of particles occurs [15]. It is still under debate if the peri-implant osteolysis is due either to an initial mechanical instability increasing the amount of generated particles and leading to loosening [16] or to an initial biological reaction of cells to particles leading to osteolysis and then mechanical instability [17]. It is then of interest to determine if low concentrations of particles, representing an early post-operative situation, can affect the bone remodeling process and more specifically the osteoclastogenesis factors produced by osteoblasts.

It has been recognized that wear particles debris are potent stimuli for osteoclast differentiation and mature osteoclast function [18]. However, only recently osteoblasts have been recognized to play a pivotal role in osteoclastogenesis process through the production of molecular factors such as RANKL, OPG, or CSF-1 [19], [20], [21], [22], [23]. Based on this new information, it has been shown that RANKL is essential to mediate the osteoclastogenic effect of PMMA [24]. In another study, OPG inhibited in vitro murine osteoclast formation induced by fluid from failed total hip arthroplasties [25]. In peri-implant tissues of patients with implant failure, high levels of RANKL was found compared to healthy subjects [26]. Macrophages were shown to be responsible for this increase.

The goal of this study is to simultaneously quantify the levels of RANKL, OPG, CSF-1 when osteoblasts are challenged with low concentrations of particles. This information would then be useful to determine if particles may be at the origin of the peri-implant osteolysis through an induction of osteoclastogenesis. The quantification of particles effect on the osteoclastogenesis process can be helpful in the search for therapeutic treatments to control the bone remodeling around orthopedic implants.

Section snippets

Ti particles

The Ti particles were purchased from Johnson Mattey company (Karlsruhe, Germany). The distribution of particle size was performed with laser diffraction by using Malvern MasterSizer equipment. The average particle size was 4.5 μm and the surface area was 0.5 m²/mg. The particles, autoclave at 135°C for 15 min, were mixed with the culture medium under sterile conditions. Based on a particle weight to medium volume ratio, a concentration of 0.01% Ti particles was prepared. One milliliter of

Results

At each time point, RANKL gene expression by osteoblasts was higher in the Ti group compared to control, with statistical significances at 24 and 48 h (p<0.01) (Fig. 1). A steady increase was observed from 8 to 48 h followed by a decrease at 72 h. A similar trend was found for the CSF-1 gene expression by osteoblasts with a statistical significance at 48 h (p<0.01). OPG gene expression was slightly higher for the Ti group compared to control until 48 h, however without statistical significance. The

Discussion

The peri-implant osteolysis is an important clinical problem, which can lead to orthopedic implant failure. In this study, we evaluated in vitro if the presence of a low-particles concentration could be involved in this problem by quantifying the production of osteoclastogenesis factors by osteoblasts.

Based on this study, low concentrations of Ti particles might have an important role in the peri-implant osteolysis as demonstrated by the increase of osteoblast gene expression for RANKL and

Conclusions

This study suggests that particles at low concentrations could be involved in the osteoclastogenesis process as shown by the upregulation of RANKL and CSF-1 in ostoeblasts challenged with Ti particles. The Ti particles may then be at the origin of the peri-implant osteolysis and early control of osteoclastogenesis could be a potential solution to decrease this problem.

Acknowledgements

This work was supported by a grant (#309) from the Leenaards Foundation.

References (45)

C. Vermes et al.
The potential role of the osteoblast in the development of periprosthetic osteolysisreview of in vitro osteoblast responses to wear debris, corrosion products, and cytokines and growth factors
J Arthroplasty
(2001)
H. Zreiqat et al.
Prosthetic particles modify the expression of bone-related proteins by human osteoblastic cells in vitro
Biomaterials
(2003)
D.D. Dean et al.
Effect of polymer molecular weight and addition of calcium stearate on response of MG63 osteoblast-like cells to UHMWPE particles
J Orthop Res
(2001)
D.P. Pioletti et al.
The effects of calcium phosphate cement particles on osteoblast functions
Biomaterials
(2000)
W.S. Simonet et al.
Osteoprotegerina novel secreted protein involved in the regulation of bone density
Cell
(1997)
D.L. Lacey et al.
Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation
Cell
(1998)
J.C. Clohisy et al.
RANKL is an essential cytokine mediator of polymethylmethacrylate particle-induced osteoclastogenesis
J Orthop Res
(2003)
T.N. Crotti et al.
Factors regulating osteoclast formation in human tissues adjacent to peri-implant bone lossexpression of receptor activator NFkappaB, RANK ligand and osteoprotegerin
Biomaterials
(2004)
C.H. Lohmann et al.
Phagocytosis of wear debris by osteoblasts affects differentiation and local factor production in a manner dependent on particle composition
Biomaterials
(2000)
J.N. Beresford et al.
Production of osteocalcin by human bone cells in vitro. Effects of 1,25(OH)2D3, 24,25(OH)2D3, parathyroid hormone, and glucocorticoids
Metab Bone Dis Relat Res
(1984)

E. Stringa et al.

Osteoblastic cells from rat long bone

I. Characterization of their differentiation in culture. Bone

(1995)

M.E. Martinez et al.

Effect of polyethylene particles on human osteoblastic cell growth

Biomaterials

(1998)

R.J. Friedman et al.

Current concepts in orthopaedics biomaterials and implant fixation

J Bone Jt Surg

(1993)

T.T. Glant et al.

Bone-resorption activity of particulate-stimulated macrophages

J Bone Miner Res

(1993)

S.B. Goodman et al.

Loosening and osteolysis of cemented joint arthroplasties

Clin Orthop Rel Res

(1997)

A.S. Shanbhag et al.

Nitric oxide release by macrophages in response to particulate wear debris

J Biomed Mater Res

(1998)

I.C. Clarke et al.

Debris-mediated osteolysis—a cascade phenomenon involving motion, wear, particulates, macrophage induction, and bone lysis

J. Yao et al.

Suppression of osteoblast function by titanium particles

J Bone Jt Surg

(1997)

D.P. Pioletti et al.

The cytotoxic effect of titanium particles phagocytosed by osteoblasts

J Biomed Mater Res

(1999)

S.Y. Kwon et al.

Titanium particles inhibit osteoblast adhesion to fibronectin-coated substrates

J Orthop Res

(2000)

H. Takei et al.

Combined effect of titanium particles and TNF-alpha on the production of IL-6 by osteoblast-like cells

J Biomed Mater Res

(2000)

D.P. Pioletti et al.

Gene expression analysis of osteoblastic cells contacted by orthopedic implant particles

J Biomed Mater Res

(2002)

Cited by (68)

An in vivo toxicity assessment of piezoelectric sodium potassium niobate [Na<inf>x</inf>K<inf>1-x</inf>NbO<inf>3</inf> (x = 0.2–0.8)] nanoparticulates towards bone tissue engineering approach
2022, Biomaterials Advances
One of the recent challenges in the design/development of prosthetic orthopedic implants is to address the concern of local/systemic toxicity of debris particles, released due to wear or degradation. Such debris particles often lead to inflammation at the implanted site or aseptic loosening of the prosthesis which results in failure of the implant during long run. Several in vitro studies demonstrated the potentiality of piezoelectric sodium potassium niobate [Na_xK_1-xNbO₃ (x = 0.2, 0.5, 0.8), NKN] as an emerging next-generation polarizable orthopedic implant. In this perspective, we performed an in vivo study to examine the local and systemic toxicity of NKN nanoparticulates, as a first report. In the present study, male Wistar rats were intra-articularly injected to the knee joint with 100 μl of NKN nanoparticulates (25 mg/ml in normal saline). After 7 days of exposure, the histopathological analyses demonstrate the absence of any inflammation or dissemination of nanoparticulates in vital organs such as heart, liver, kidney and spleen. The anti-inflammatory cytokines (IL-4 and IL-10) profile analyses suggest the increased anti-inflammatory response in the treated rats as compared to non-injected (control) rats, preferably for the sodium and potassium rich NKN i.e., Na_0.8K_0.2NbO₃ and Na_0.2K_0.8NbO₃. The biochemical analyses revealed no pathological changes in the liver and kidney of particulate treated rats. The present study is the first proof to confirm the non-toxic nature of NKN nanoparticulates which provides a step forward towards the development of prosthetic orthopedic implants using biocompatible piezoelectric NKN ceramics.
A review on osteoclast diseases and osteoclastogenesis inhibitors recently developed from natural resources
2020, Fitoterapia
Natural products have been investigated as potential candidates of novel therapeutics and play a crucial role in advanced medicinal drugs. Natural resources, including local medicinal plants (especially folk medicinal plants), animals, bacteria, and fungi have been used for more than a century, and are precious gifts from nature, providing potential medicines with high safety. Osteoclast-related diseases, such as osteoporosis, rheumatoid arthritis, Paget's disease, osteoclastoma, and periprosthetic osteolysis, are currently the most common reasons for bone inflammation, pain and fractures, resulting in low quality of life. However, the curative effects of current therapeutic drugs for these osteoclast-related diseases are limited, and long-term treatment is needed. Further, in severe cases, surgical treatments are necessary, which may cause unaffordable expenses and subsequent influences such as neuralgia, mental stress, and even development of cancer. Thus, safer inhibitors and potential drugs with enhanced curative effects and quick relief are needed to treat patients with osteoclast diseases. This review aims to introduce the main osteoclast-related diseases and some of the recently developed naturally sourced inhibitors against osteoclastogenesis, also it is desired to attract people's attention on using widely available natural resources for the evolution of new types of osteoclast inhibitors with minimal or no side-effects upon long-term treatments.
Cepharanthine ameliorates titanium particle-induced osteolysis by inhibiting osteoclastogenesis and modulating OPG/RANKL ratio in a murine model
2019, Biochemical and Biophysical Research Communications
Citation Excerpt :
These wear particles would induce an inflammatory response by recruiting cells to secrete chemokines and pro-inflammatory cytokines, such as TNF-α and IL-1β [2,3]. Subsequently, the inflammatory response stimulated osteoclastogenesis and elevated bone resorption in the periphery of implanted prostheses, resulting in periprosthetic osteolysis [4]. Thus, inhibition of excessive osteoclast formation is a potential way to prevent periprosthetic loosening.
Periprosthetic asepteic loosening, caused by wear debris, is one of the most severe complications, generally resulting in implant failure. Extensive osteoclast formation and activation are considered as the cause for periprosthetic osteolysis. However, few approaches have been approved to be used for preventing early-stage periprosthetic osteolysis. In this study, we investigated the preventive effects of CEP on titanium particles-induced osteolysis in a murine calvaria model. This inhibitory effect was confirmed to be realized by attenuating osteoclastogenesis in vivo. In addition, CEP markedly reduced wear particles-induced elevation of receptor activator of nuclear factor kappa B ligand (RANKL)/Osteoprotegerin (OPG) ratio in vivo. In conclusion, these data concluded that CEP demonstrated a preventive effect of CEP on titanium particles induced osteolysis, suggesting that CEP might be a novel therapeutic for periprosthesis loosening.
Emodin attenuates titanium particle-induced osteolysis and RANKL-mediated osteoclastogenesis through the suppression of IKK phosphorylation
2018, Molecular Immunology
Aseptic loosening due to wear particles is a serious challenge for orthopedic surgeons, sabotaging the long-term success of total joint arthroplasty. The existing treatments for aseptic loosening are still far from satisfactory, necessitating more aggressive drug exploration. Here, we examined the effect of emodin on titanium particle-induced osteolysis and further investigated its underlying mechanism in vivo and in vitro. Thirty-two C57BL/6 mice were randomly assigned into four groups: the Sham group (sham operation with vehicle injection), Vehicle group (titanium particle treatment with vehicle injections), Low group (titanium particle treatment with injections of 10 mg/kg/day emodin) and High group (titanium particle treatment with injections of 50 mg/kg/day emodin). Micro-CT scanning and histological analysis revealed that after emodin injections, the inflammatory response and bone destruction were markedly ameliorated. TRAP staining showed that osteoclast numbers were also dramatically reduced. Throughout the in vitro culture period, emodin significantly decreased the bone resorption area, number of osteoclasts and formation of F-actin rings. Mechanistic studies suggested that reduced NF-κB signaling might be mediating the inhibitory effects of emodin. Collectively, our findings suggest that emodin, a natural product extracted from Rheum palmatum, may be developed as a promising candidate for the treatment of wear particle-induced osteolysis and subsequent aseptic loosening.
NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases
2017, Advances in Protein Chemistry and Structural Biology
Citation Excerpt :
Inhibition of NF-κB activity in the MSCs exposed to wear particles mitigated the reduced bone formation (Lin et al., 2015). The paracrine regulators including IL-8, GM-CSF (Haleem-Smith et al., 2012), M-CSF, and RANKL (Pioletti & Kottelat, 2004) are also upregulated in OB or MSC exposed to wear particles, which could further enhance inflammation and the osteolytic process. Aging is associated with chronic inflammation and increased reactive oxygen species.
Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system.
The two faces of metal ions: From implants rejection to tissue repair/regeneration
2016, Biomaterials
Citation Excerpt :
Some in vitro studies have addressed the effect of Ti microparticles on bone remodeling. Osteoblasts incubated with very high concentrations of Ti microparticles (30,000 μg/L) for 48 h led to increased production of osteoclastogenesis factors, such as receptor activator of nuclear factor kappa-B ligand (RANKL) and CSF-1 [140]. Additionally, bone marrow stromal/stem cells (BMSCs) exposed to Ti microparticles presented impaired osteogenic differentiation and increased production of IL-8 [141], a chemokine that is involved in the recruitment of neutrophils and is overexpressed in periprosthetic tissues of aseptic loosening patients [142].
The paradigm of metallic ions as exclusive toxic agents is changing. During the last 60 years, knowledge about toxicological and immunological reactions to metal particles and ions has advanced considerably. Hip prostheses, namely metal-on-metal bearings, have prompted studies about excessive and prolonged exposure to prosthetic debris. In that context, the interactions of metal particles and ions with cells and tissues are mostly harmful, inducing immune responses that lead to osteolysis and implant failure.
However, in the last decade, new strategies to promote immunomodulation and healing have emerged based on the unique properties of metallic ions. The atom-size and charge enable ions to interact with key macromolecules (e.g. proteins, nucleic acids) that affect cellular function. Moreover, these agents are inexpensive, stable and can be integrated in biomaterials, which may open new avenues for a novel generation of medical devices.
Herein, orthopedic devices are discussed as models for adverse responses to metal ions, and debated together with the potential to use metal ions-based therapies, thus bridging the gap between unmet clinical needs and cutting-edge research. In summary, this review addresses the two “faces” of metallic ions, from pathological responses to innovative research strategies that use metal ions for regenerative medicine.

View all citing articles on Scopus

View full text

The influence of wear particles in the expression of osteoclastogenesis factors by osteoblasts

Abstract

Introduction

Section snippets

Ti particles

Results

Discussion

Conclusions

Acknowledgements

J Arthroplasty

Biomaterials

J Orthop Res

Biomaterials

Cell

Cell

J Orthop Res

Biomaterials

Biomaterials

Metab Bone Dis Relat Res

I. Characterization of their differentiation in culture. Bone

Biomaterials

Current concepts in orthopaedics biomaterials and implant fixation

J Bone Jt Surg

Bone-resorption activity of particulate-stimulated macrophages

J Bone Miner Res

Loosening and osteolysis of cemented joint arthroplasties

Clin Orthop Rel Res

Nitric oxide release by macrophages in response to particulate wear debris

J Biomed Mater Res

Debris-mediated osteolysis—a cascade phenomenon involving motion, wear, particulates, macrophage induction, and bone lysis

Suppression of osteoblast function by titanium particles

J Bone Jt Surg

The cytotoxic effect of titanium particles phagocytosed by osteoblasts

J Biomed Mater Res

Titanium particles inhibit osteoblast adhesion to fibronectin-coated substrates

J Orthop Res

Combined effect of titanium particles and TNF-alpha on the production of IL-6 by osteoblast-like cells

J Biomed Mater Res

Gene expression analysis of osteoblastic cells contacted by orthopedic implant particles

J Biomed Mater Res