Jan 15, 2004 - 1Department of Orthopaedic Surgery, Wayne State University School of Medicine, Detroit, MI, USA; and 2The Center for Musculoskeletal ...
Gene Therapy (2004) 11, 402–407 & 2004 Nature Publishing Group All rights reserved 0969-7128/04 $25.00 www.nature.com/gt
REVIEW
Aseptic loosening PH Wooley1,3 and EM Schwarz2,4 1
Department of Orthopaedic Surgery, Wayne State University School of Medicine, Detroit, MI, USA; and 2The Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, USA
Although total joint replacement surgery is one of the most successful clinical procedures performed today, bone loss around knee and hip implants (osteolysis), resulting in aseptic loosening of the prosthesis, remains a major problem for many patients. Over the last decade much has been learned about this process, which is caused by wear debris particles that simulate a local inflammatory response and osteoclastic bone resorption. Aseptic loosening cannot be
prevented or treated by existing nonsurgical methods. Gene transfer, however, offers novel possibilities. Here, we review the current state of the field and the experimental gene therapy approaches that have been investigated toward a solution to aseptic loosening of prosthetic implants. Gene Therapy (2004) 11, 402–407. doi:10.1038/sj.gt.3302202 Published online 15 January 2004
Keywords: prosthesis; bone; inflammation; osteoclast; osteolysis
Introduction Degenerative and inflammatory arthritis are disabling conditions with a high incidence in the general population. Orthopedic surgical procedures have proven highly successful in the treatment of severe joint destruction secondary to degenerative and inflammatory arthritis, and the number of orthopedic surgical procedures continues to increase annually. Total hip and knee replacement surgery usual results marked symptomatic relief with substantial functional improvement. However, the benefits of prosthetic implants must be considered in the light of a number of possible complications. While failure due to sepsis, fracture, and dislocation have become relatively rare, failure secondary to aseptic loosening has become increasingly more important, and appears likely to increase in prevalence. It is estimated that over 25% of all prosthetic implants will demonstrate findings of aseptic loosening,1–4 often leading to the need for surgical revision. Initially, the term ‘cement disease’ was coined to characterize aseptic loosening.5 However, it is now known that any type of particulate debris, including that generated by poor surgical technique, loss of mechanical fixation of the polymethylmethacrylate (PMMA) bone cement, or wear at the ultra-high molecular polyethylene (UHMWPE)– metal interface may lead to the aseptic loosening process. Fragmentation of PMMA and abrasion of polyethylene may act synergistically, since PMMA debris particles may become entrapped in the articular surface, creating polyethylene particles from the resulting wear of the UHMWPE implant.6 This wear debris appears to provoke diverse biological effects, including granuloma
Correspondence: PH Wooley, Department of Orthopaedic Surgery, Wayne State University School of Medicine, 4707 St Antoine Blvd, Detroit, MI 48201, USA 3 PW is supported by a VA Merit Award and a grant from OREF 4 ES is supported by NIH PHS Grants AR45971, AR46545
formation, inflammatory cell influx, bone resorption, and eventually osteolysis and loss of the prosthesis support.7
Pathogenesis of aseptic loosening The precise etiology of aseptic loosening still remains unclear. The tissue from the areas of osteolysis shows a synovial-like layer at the cement surface and the presence of macrophages and foreign-body giant cells invading the femoral cortices. The appearance of the periprosthetic membrane at the cement/bone interface shares some histological characteristics of both rheumatoid arthritis (RA) and a foreign body reaction.8 Microscopic examination of specimens obtained at revision surgery of failed hip replacements has revealed a varied cellular composition of the periprosthetic membrane, with histiocytes, giant cells, lymphocytes, plasma cells and neutrophils, although quantitative analysis of cell types present in this tissue shows heterogeneity between different individuals.9,10 Areas around the loosened, cemented stems were frequently characterized as aggressive granulomatous lesions consisting of wellorganized tissue containing histiocytic–monocytic and fibroblastic reactive zones. Furthermore, immunohistological evaluation has revealed the presence of multinucleated giant cells and C3bi-receptor bearing phagocytic cells.11 Particles of acrylic cement and shards of polyethylene appear incorporated into the histiocyte/ macrophage or giant cell population, resulting in ‘foci’ of cellular activity within the periprosthetic membrane.12,13 Phagocytes in the tissue adjoining the implant site engulf small particles, and since plastics and metal are impervious to enzymatic destruction, these particles ‘frustrate’ the degradative function of these cells. Repeated phagocytosis of particles results in activated cells that secrete proinflammatory cytokines and proteolytic enzymes, both of which are known to both damage bone and cartilage, and activate immune cells. In particular, interleukin 1 (IL-1) and tumor necrosis factor
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(TNFa) are potent mediators of bone resorption,14–18 and recently, the immune-activating cytokines PDGF and IL11 have also been identified within the periprosthetic tissue.19,20 These cytokines provide activation signals to lymphocytes,21 and in turn, the lymphocyte-derived cytokines interleukin 2 (IL-2), interleukin 6 (IL-6) and gamma interferon (IFN-g) may influence osteoclastic activity and bone remodeling.22 Studies using an in vitro osteoclast model have suggested that the response to PMMA may directly contribute to the process of bone resorption.23 UHMWPE wear has been significantly correlated with frequency and size of osteolytic lesions24 and may also act to inhibit biosynthetic pathways of bone and mesenchymal tissue.25 Macrophages induced to phagocytose biomaterials (UHMWPE, PMMA and orthopedic alloys) differentiated into osteoclastic cells capable of extensive lacunar bone resorption during bone culture26,27 and also express high levels of the osteoclast activating cytokine M-CSF (CSF-1).28 Both UHMWPE and titanium (Ti-6-4) particles significantly enhanced in vitro macrophage cytokine (TNFa, IL-1, IL8) release in a dose-dependent manner,29 and explant cultures of periprosthetic membranes and synovial tissue derived from osteoarthritic patients undergoing revision for cemented hip implant failure produce IL-1, TNFa, IL-8, prostaglandin E2 and nitric oxide,9,30–33 suggesting immuno-inflammatory activity within the implanted joint. The nature of the dominant wear particle may be critical to the response in an individual patient, since cobalt chromium (Co-Cr) may result in a dominant TNFa release over IL-1 or IL-6 production,34 while Ti-6-4 particles appear to mediate an IL-6 response.35–37
Osteolysis in aseptic loosening The release of inflammatory mediators results in chronic inflammation and tissue damage that deteriorate the supporting bone, with adverse effects on prosthesis fixation.38,39 Normally, bone mass is determined by the delicate balance that exists between formation and loss. Osteoblastic cells of mesenchymal origin synthesize and deposit bone matrix and increase bone mass. Osteoclastic cells are large, multinucleated phagocytes of hematopoietic origin that resorb bone upon activation. Recent advances in bone biology have focused studies on the pathogenesis of aseptic loosening beyond the influence of the classical inflammatory cytokines in response to wear debris. Two important regulators of osteoclast differentiation and activation have been identified; RANKL40–42 and osteoprotegerin (OPG).43 RANKL, also known as OPGL44 and ODF,45 is a TNF-related cytokine that is produced by marrow stromal cells and osteoblasts41,42 Mice lacking RANKL have defects in osteoclastogenesis that leads to severe osteopetrosis.46 OPG is a secreted TNF receptor (TNFR)-related protein that binds to and neutralizes RANKL bioactivity. Mice lacking OPG develop severe osteoporosis and have brittle bones that spontaneously fracture.47 These data indicate that OPG and RANKL interact as key regulators of osteoclastogenesis and bone resorption.41,42 RANKL binds to RANK (receptor activator of nuclear factor kappa B),48 a member of TNF receptor super family, which is present on osteoclasts and their precursors49 and initiates osteoclastogenesis after ligation with
RANKL or agonistic anti-RANK antibodies.40–42,48,50 Dougall et al51 have determined an essential role of RANK in regulating osteoclastogenesis in RANK gene knockout (RANK/) mice. Li et al52 reported that osteoclastogenic effects of RANKL cannot be reproduced in RANK/ mice suggesting that RANK serves as the sole osteoclast receptor for RANKL and controls osteoclast development and activation.53–54 In addition, failure of RANK/ mice to mount a significant osteoclastic response in the presence of experimental inflammatory arthritis further supports the concept that RANK plays a gate-keeping role in controlling osteoclastogenesis.46 As part of the inflammation process, genes of cytokines, chemokines, growth factors, cell adhesion molecules, and some acute-phase proteins will be turned on and frequently overexpressed. Part of this genetic regulation is controlled by nuclear factor kappa B (NFkB).55–57 It is becoming evident that NF-kB is a key factor for the development of osteoclastogenesis. Two recent studies58,59 found that the double-knock out of NF-kB1 and NF-kB2 in mice resulted in an unexpected phenotype. These animals showed an impaired macrophage functions and failed to generate mature osteoclasts, which resulted in severe osteopetrosis. Additional studies suggested that this abnormality occurred as a result of a defect either during osteoclast precursor cell differentiation or during the maturation of osteoclasts. Obviously, this double knockout experiment could provide a relevant model to study the etiology of osteoporosis and raise new directions in regulation of osteoclastogenesis.58 It is possible that the osteoclastogenic activity of several cytokines, such as TNF, IL-1 might be ameliorated by prevention of NF-kB binding to their respective binding sites of the promoter sequence. Regulation of NF-kB activation represents a powerful therapeutic strategy for reducing inflammatory tissue damage, but complete and persistent blockage of NF-kB activation could lead to immune deficiency and cell death. Glucocorticoids are widely prescribed immunosuppressive and anti-inflammatory drugs, whose antiinflammatory effects are achieved either by glucocorticoid receptor-mediated interference of NF-kB DNAbinding activity or by enhanced synthesis of IkB, which would compromise the nuclear translocation and DNA binding of NF-kB.60,61 The liberal use of glucocorticoids, however, is limited because of their well-known side effects on endocrine function and metabolism. A more rational and promising strategy to block NF-kB activation is the development of compounds that potentially targets a specific point in the signaling pathway without influencing other cellular biological functions.
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Animal models A prerequisite for a therapeutic or gene therapy is the development of an animal model that recapitulates the etiology or some salient features of the human disease. For obvious reasons, the early models of aseptic loosening involved an implant in the rat62 and dog.63 However, once an implant is integrated into bone to achieve true fixation, clinical aseptic loosening takes at least 5 years. This shortcoming is also true in the animal models, as demonstrated by a modified rat model that incorporated a running wheel for 2 h/day for 5 days/week.64 Despite Gene Therapy
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the increased mechanical load, which contributed to the development of a periprosthetic membrane, there was no evidence of implant loosening after 6 months. Based on the limitations of the implant models, investigators have decided to focus on the biology of wear debris-induced osteolysis independent of the critical mechanical and biomechanical components of aseptic loosening. To this end, two mouse models have been developed that permit the use of exquisite molecular reagents and genetically defined strains, together with highly quantitative outcome measures of osteoclast formation and bone resorption. The first is the air pouch model in which particulate wear debris is coimplanted with a bone substrate into a subcutaneous space.65 The wear debris stimulates an inflammatory reaction that culminates in the genesis of an erosive tissue that is similar to a periprosthetic membrane. A murine calvaria model has also been established that involved the surgical implantation of wear debris particles on top of the skull.66,67 Again, the wear debris induces an intense inflammatory reaction that leads to osteoclastic formation and osteolysis within 1 week. By utilizing mice genetically defective in TNF68 and RANK69 signaling, the first in vivo evidence in support of the proinflammatory osteolysis as the causes of aseptic loosening was generated. Furthermore, similar findings from studies in which wild-type mice were treated with TNFR:Fc70 and RANK:Fc69 demonstrated the potential of a therapeutic agent or gene therapy for aseptic loosening.
Gene therapy It has been proposed that pharmacological intervention targeted towards the macrophage may provide a means to slow the response to wear debris.71 However, delivering adequate levels of cell-specific therapy to the site of periprosthetic inflammation, without undesirable systemic effects, represents a considerable challenge. Local cytokine inhibition is a potential therapy that may reduce inflammation in the periprosthetic tissue, and several biological mediators have known been identified as useful for clinical applications. In particular, IL-1 receptor antagonist protein (IL-1Ra or IRAP) has been successful in reducing inflammation,72,73 and the antiinflammatory cytokine IL-10 appears to possess the capacity to reduce cell-mediated reactions in inflammation.74,75 The delivery of appropriate doses of proinflammatory cytokine inhibitors to the periprosthetic tissue remains a problem. However, recent advances in gene therapy techniques76,77 suggest that viral vectors may be capable of delivering anti-inflammatory cytokine genes to the periprosthetic tissues, which could control the local reaction and extend the life of the prosthesis. We have conducted experiments using the particle-stimulated murine air pouch model to evaluate the potential for gene therapy to treat inflammation provoked by orthopedic wear debris. In our initial study,65 retroviral vectors encoding human IL-1Ra and the human tumor necrosis factor receptor (TNF-R) were evaluated using this in vivo model. Air pouches established in BALB/c mice were injected with PMMA particles to provoke an inflammatory reaction, and transduced with contrakine genes or control retroviruses. Pouch membranes and fluids were harvested after 48 h, and retroviral insertion Gene Therapy
and contrakine gene incorporation were assessed in DNA from pouch membranes using polymerase chain reactions (PCR). ELISA assays were conducted to determine the level of contrakine and inflammatory cytokine production. Image analysis performed on pouch membrane sections to evaluate thickness of the air pouch membrane and the magnitude and morphology of the cellular infiltrate. Positive PCR reactions for IL-1Ra and neo genes were observed in DNA extracted from the membrane of retroviral-infected pouches, while DNA extracted from either inflammatory cells present in pouch fluid, or control pouch membranes, remained negative for either gene. This result suggests that this replication-deficient vector may achieve incorporation at a local site without widespread infection of the evolving inflammatory infiltrate, an important observation when considering this approach for clinical use. ELISA assays revealed the presence of human IL-1Ra in pouch fluid from DFG-IRAP-neo transduced mice, but not control animals. Histological evaluation indicated that the IL1Ra gene transfer was associated with markedly decreased inflammation in the model, with resolution of the edematous phase of the reaction, decreased pouch fluid accumulation, and lowered macrophage influx. The results suggest that the air pouch model represents a useful tool to evaluate gene therapy, and demonstrate that IL-1Ra gene therapy may be an appropriate therapeutic approach to inflammation. Similar studies have been performed to evaluate the effects of TNF-R gene therapy in the calvaria model using a recombinant adenoviral vector.78 While the experiments demonstrated the predicted antiresorptive effects in nude mice, the study was highlighted by two additional findings. The first was that local gene delivery was not significantly more efficacious than systemic gene therapy, and that efficacy was correlated to the concentration of TNFR:Fc/ml in serum. However, the more important finding was the tremendous inflammatory reaction from the adenoviral vector alone, which induced an osteolytic response that significantly exceeded that of the wear debris when placed directly on the calvaria of wild-type mice. This finding is consistent with many previous studies regarding the immunogenicity of adenoviral vectors and warns against its clinical use. We have extended this research to evaluate viral IL-10 (vIL-10) in these models.79,80 In the air pouch study, an investigation of mRNA expression using real-time PCR was conducted to determine whether anti-inflammatory gene therapy affects cytokine gene expression. IL-1, IL-6 and TNF gene expression were readily detected by the technique, and IL-1 was observed to be the predominant cytokine expressed in response to UHMWPE particle stimulation. There were only low amounts of IL-4, and IL-10 expressed, and IL-2, IL-5 and IFNg were not detectable. The transfer of the viral IL-10 gene significantly diminished IL-1 mRNA expression at all time points investigated, and TNFa and IL-6 mRNA levels in pouch membranes following viral IL-10 or IL-1Ra transduction was also significantly decreased. Interestingly, a significant higher expression of TGF was detected in the pouches with IL-1Ra gene insertion, but no effects of IL-1Ra and vIL-10 gene transfer on IL-4 and mouse IL-10 expression was observed. Histological assessments revealed that pouches transduced with vIL-10 or IL-1Ra exhibited a 40% reduction in inflam-
Aseptic loosening PH Wooley and EM Schwarz
matory cell infiltration when compared with nonviral controls or LacZ-transduced membranes. Further, esterase staining indicated that both vIL-10 and IL-1Ra gene therapies dramatically decreased macrophage presentation in the pouch membranes. The calvaria study corroborated these findings by independently demonstrating that gene delivery of vIL-10 inhibits three processes critically involved in periprosthetic osteolysis wear debris-induced proinflammatory cytokine production, osteoclastogenesis, and osteolysis. Encouraged by our findings that anti-inflammatory gene therapy appears to have ameliorating effects on particle-induced inflammation, we have recently extended this approach to the inhibition of osteoclastogenesis. There are reports that inflammatory osteoclastogenesis can be blocked by neutralizing IL-1/TNF bioactivity both in vivo81–83 and in vitro.84 An emerging concept is that RANK may act as a common mediator for cytokines relevant osteoclastogenesis.41,52 In supporting this concept, a recent study52 demonstrated that no osteoclastogenesis and bone resorption can be induced in RANK/ mice when treated with IL-1, as shown by the complete absence of TRAP þ and cathepsin K þ osteoclasts in their calvaria. Therefore, the osteoclastogenic activity of IL-1 is mediated exclusively through RANK. The interaction between TNF and RANK is complex. One recent study showed that TNF induced osteoclastogenesis needs the assistance of basal amount of RANKL, perhaps through their synergistic effects on activation of NF-kB, a signaling pathway essential for osteoclastogenesis.85 Because a small amount of RANKL is sufficient to synergize with TNF to promote osteoclastogenesis, TNF may be a more convenient clinical target than RANKL in arresting inflammatory osteoclastogenesis. Another report also demonstrated52 that the rare appearance of TRAP þ and cathepsin K þ osteoclasts on the bone surface could be induced in the calvaria of RANK/ mice treated with TNF at high dose (1.0 mg/kg body wt per day). However, the osteoclast-like cells are occasionally found within the calvaria near the site of administration. These data raised the possibility that TNF might trigger an alternative compensatory pathway leading to osteoclast formation in the absence of RANK, presumably by activation of either TNFR1 or TNFR2. Since TNF and RANKL are considerably overlapping in their signaling pathway,86 we postulated that during aseptic loosening, RANKL and TNF might synergistically orchestrate enhanced osteoclastogenesis via cooperative mechanisms. To investigate the potential of the RANKL system as a therapeutic target in aseptic loosening, we investigated whether an in vivo gene transfer of OPG using an adeno-associated virus (AAV)-vector exerted protective effects against orthopedic wear debris-induced bone loss in a murine model of osteolysis.87 Bone tissue was implanted into established pouches on BALB/ c mice, followed by the introduction of ultra-high molecular polyethylene (UHMWPE) particles to provoke inflammation and osteolysis. The viruses encoding human OPG gene (rAAV-hOPG) or b-galactosidase marker gene (rAAV-LacZ) were injected into the air pouches, and the tissue harvested 7 days after viral infection for histological and molecular analyses. Successful transgene expression was confirmed by the detection of OPG by ELISA and positive X-gal staining of pouch tissue (LacZ). Real-time PCR indicated significant diminish-
ment of mRNA expression of osteoclast markers in OPGtransduced pouches compared with rAAV-LacZ-transduced pouches. The transduction and expression of OPG also markedly decreased the gene copies of the biological receptor for osteoclast differentiation factor (RANK). The expression of OPG in the bone-implanted pouch reduced bone calcium release by a mean of 39% compared with the calcium release in other two groups. Computerized image analysis revealed that expression of OPG significantly protected against bone collagen loss. We also evaluated the effects of ex vivo88 and in vivo89 OPG gene therapy in the calvaria model of wear debris-induced osteolysis. Again the results were similar to the data obtained in the air pouch model and support the hypothesis that RANKL is the final effector of osteoclastogenesis and bone resorption. These preliminary results provide encouraging preclinical data for OPG mediated therapy in aseptic loosening, and overall, the data suggest that gene therapy may be an appropriate technique to provide local anti-inflammatory and antibone resorptive activity at the prosthesis–bone interface.
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Future directions Significant evidence now exists indicating that aseptic loosening of orthopedic implants is caused by wear debris-induce inflammation, osteoclastogenesis and subsequent osteolysis around the prosthesis. Additionally, several preclinical studies have demonstrated the efficacy of contrakine and anti-osteoclastic gene therapy approaches in small animal models. Future studies aimed at evaluated these vectors in large animal models (eg canine) with quantitative longitudinal radiologic outcome measures and biomechanical testing are warranted.
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Gene Therapy
