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1.  Structural damage in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: traditional views, novel insights gained from TNF blockade, and concepts for the future 
Arthritis Research & Therapy  2011;13(Suppl 1):S4.
Structural changes of bone and cartilage are a hallmark of inflammatory joint diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Despite certain similarities – in particular, inflammation as the driving force for structural changes – the three major inflammatory joint diseases show considerably different pathologies. Whereas RA primarily results in bone and cartilage resorption, PsA combines destructive elements with anabolic bone responses, and AS is the prototype of a hyper-responsive joint disease associated with substantial bone and cartilage apposition. In the present review we summarize the clinical picture and pathophysiologic processes of bone and cartilage damage in RA, PsA, and AS, we describe the key insights obtained from the introduction of TNF blockade, and we discuss the future challenges and frontiers of structural damage in arthritis.
doi:10.1186/1478-6354-13-S1-S4
PMCID: PMC3123965  PMID: 21624183
2.  Arthritis Gene Therapy and its Tortuous Path into the Clinic 
Arthritis is a disease of joints. The biology of joints makes them very difficult targets for drug delivery in a manner that is specific and selective. This is especially true for proteinaceous drugs (“biologics”). Gene transfer is the only technology that can solve the delivery problem in a clinically reasonable fashion. There is an abundance of pre-clinical data confirming that genes can be efficiently transferred to tissues within joints by intra-articular injection using a variety of different vectors in conjunction with ex vivo and in vivo strategies. Using the appropriate gene transfer technologies, long-term, intra-articular expression of anti-arthritic transgenes at therapeutic concentrations can be achieved. Numerous studies confirm that gene therapy is effective in treating experimental models of rheumatoid arthritis (RA) and osteoarthritis (OA) in the laboratory. A limited number of clinical trials have been completed, which confirm safety and feasibility but only three protocols have reached Phase II; as yet, there is no unambiguous evidence of efficacy in human disease. Only two clinical trials are presently underway, both Phase II studies using allogeneic chondrocytes expressing TGF-β1 for the treatment of OA. Phase I studies using adeno-associated virus to deliver IL-1Ra in OA and IFN-β in RA are going through the regulatory process. It is to be hoped that the recent successes in treating rare, Mendelian diseases by gene therapy will lead to accelerated development of genetic treatments for common, non-Medelian diseases, such as arthritis.
doi:10.1016/j.trsl.2013.01.002
PMCID: PMC3602127  PMID: 23369825
3.  Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis 
Arthritis Research  1999;1(1):81-91.
Destruction of cartilage and bone are hallmarks of human rheumatoid arthritis (RA), and controlling these erosive processes is the most challenging objective in the treatment of RA. Systemic interleukin-4 treatment of established murine collagen-induced arthritis suppressed disease activity and protected against cartilage and bone destruction. Reduced cartilage pathology was confirmed by both decreased serum cartilage oligomeric matrix protein (COMP) and histological examination. In addition, radiological analysis revealed that bone destruction was also partially prevented. Improved suppression of joint swelling was achieved when interleukin-4 treatment was combined with low-dose prednisolone treatment. Interestingly, synergistic reduction of both serum COMP and inflammatory parameters was noted when low-dose interleukin-4 was combined with prednisolone. Systemic treatment with interleukin-4 appeared to be a protective therapy for cartilage and bone in arthritis, and in combination with prednisolone at low dosages may offer an alternative therapy in RA.
Introduction:
Rheumatoid arthritis (RA) is associated with an increased production of a range of cytokines including tumour necrosis factor (TNF)-α and interleukin (IL)-1, which display potent proinflammatory actions that are thought to contribute to the pathogenesis of the disease. Although TNF-α seems to be the major cytokine in the inflammatory process, IL-1 is the key mediator with regard to cartilage and bone destruction. Apart from direct blockade of IL-1/TNF, regulation can be exerted at the level of modulatory cytokines such as IL-4 and IL-10. IL-4 is a pleiotropic T-cell derived cytokine that can exert either suppressive or stimulatory effects on different cell types, and was originally identified as a B-cell growth factor and regulator of humoral immune pathways. IL-4 is produced by activated CD4+ T cells and it promotes the maturation of Th2 cells. IL-4 stimulates proliferation, differentiation and activation of several cell types, including fibroblasts, endothelial cells and epithelial cells. IL-4 is also known to be a potent anti-inflammatory cytokine that acts by inhibiting the synthesis of proinflammatory cytokines such as IL-1, TNF-α, IL-6, IL-8 and IL-12 by macrophages and monocytes. Moreover, IL-4 stimulates the synthesis of several cytokine inhibitors such as interleukin-1 receptor antagonist (IL-1Ra), soluble IL-1-receptor type II and TNF receptors IL-4 suppresses metalloproteinase production and stimulates tissue inhibitor of metalloproteinase-1 production in human mononuclear phagocytes and cartilage explants, indicating a protective effect of IL-4 towards extracellular matrix degradation. Furthermore, IL-4 inhibits both osteoclast activity and survival, and thereby blocks bone resorption in vitro. Of great importance is that IL-4 could not be detected in synovial fluid or in tissues. This absence of IL-4 in the joint probably contributes to the disturbance in the Th1/Th2 balance in chronic RA.
Collagen-induced arthritis (CIA) is a widely used model of arthritis that displays several features of human RA. Recently it was demonstrated that the onset of CIA is under stringent control of IL-4 and IL-10. Furthermore, it was demonstrated that exposure to IL-4 during the immunization stage reduced onset and severity of CIA. However, after cessation of IL-4 treatment disease expression increased to control values.
Aims:
Because it was reported that IL-4 suppresses several proinflammatory cytokines and matrix degrading enzymes and upregulates inhibitors of both cytokines and catabolic enzymes, we investigated the tissue protective effect of systemic IL-4 treatment using established murine CIA as a model. Potential synergy of low dosages of anti-inflammatory glucocorticosteroids and IL-4 was also evaluated.
Methods:
DBA-1J/Bom mice were immunized with bovine type II collagen and boosted at day 21. Mice with established CIA were selected at day 28 after immunization and treated for days with IL-4, prednisolone, or combinations of prednisolone and IL-4. Arthritis score was monitored visually. Joint pathology was evaluated by histology, radiology and serum cartilage oligomeric matrix protein (COMP). In addition, serum levels of IL-1Ra and anticollagen antibodies were determined.
Results:
Treatment of established CIA with IL-4 (1 μg/day) resulted in suppression of disease activity as depicted in Figure 1. Of great interest is that, although 1 μg/day IL-4 had only a moderate effect on the inflammatory component of the disease activity, it strongly reduced cartilage pathology, as determined by histological examination (Fig. 1). Moreover, serum COMP levels were significantly reduced, confirming decreased cartilage involvement. In addition, both histological and radiological analysis showed that bone destruction was prevented (Fig. 1). Systemic IL-4 administration increased serum IL-1Ra levels and reduced anticollagen type II antibody levels. Treatment with low-dose IL-4 (0.1 μg/day) was ineffective in suppressing disease score, serum COMP or joint destruction. Synergistic suppression of both arthritis severity and COMP levels was noted when low-dose IL-4 was combined with prednisolone (0.05 mg/kg/day), however, which in itself was not effective.
Discussion:
In the present study, we demonstrate that systemic IL-4 treatment ameliorates disease progression of established CIA. Although clinical disease progression was only arrested and not reversed, clear protection against cartilage and bone destruction was noted. This is in accord with findings in both human RA and animal models of RA that show that inflammation and tissue destruction sometimes are uncoupled processes. Of great importance is that, although inflammation was still present, strong reduction in serum COMP was found after exposure to IL-4. This indicated that serum COMP levels reflected cartilage damage, although a limited contribution of the inflamed synovium cannot be excluded.
Increased serum IL-1Ra level (twofold) was found after systemic treatment with IL-4, but it is not likely that this could explain the suppression of CIA. We and others have reported that high dosages of IL-1Ra are needed for marked suppression of CIA. As reported previously, lower dosages of IL-4 did not reduce clinical disease severity of established CIA. Of importance is that combined treatment of low dosages of IL-4 and IL-10 appeared to have more potent anti-inflammatory effects, and markedly protected against cartilage destruction. Improved anti-inflammatory effect was achieved with IL-4/prednisolone treatment. In addition, synergistic effects were found for the reduction of cartilage and bone destruction. This indicates that systemic IL-4/prednisolone treatment may provide a cartilage and bone protective therapy for human RA.
Effects in mice of treatment with interleukin-4 or control on disease activity, cartilage damage and bone destruction. Mice were treated intraperitoneally for 7 days with either vehicle (control) or 1 μg/day interleukin-4 (IL-4). CIA, collagen-induced arthritis. *P < 0.05, versus control, by Mann-Whitney U test.
PMCID: PMC17779  PMID: 11056663
bone destruction; cartilage oligomeric matrix protein levels; collagen-induced arthritis; interleukin-4; prednisolone
4.  Elucidation of the potential roles of matrix metalloproteinases in skeletal biology 
Irreversible destruction of joint structures is a major feature of osteoarthritis and rheumatoid arthritis. Fibrillar collagens in bone, cartilage and other soft tissues are critical for optimal joint form and function. Several approaches can be used to ascertain the role of collagenases, matrix metalloproteinases, in proteolysis of joint collagens in arthritis. These approaches include identifying spontaneous genetic disorders of the enzymes and substrates in humans and animals, as well as engineering mutations in the genes that encode these proteins in mice. Insights gained from such studies can be used to design new therapies to interrupt these catabolic events.
doi:10.1186/ar600
PMCID: PMC154421  PMID: 12716440
arthritis; bone remodeling; collagenases; collagens; skeletal development
5.  Gene therapy in animal models of rheumatoid arthritis: are we ready for the patients? 
Arthritis Research & Therapy  2004;6(5):183-196.
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints, with progressive destruction of cartilage and bone. Anti-tumour necrosis factor-α therapies (e.g. soluble tumour necrosis factor receptors) ameliorate disease in 60–70% of patients with RA. However, the need for repeated systemic administration of relatively high doses in order to achieve constant therapeutic levels in the joints, and the reported side effects are downsides to this systemic approach. Several gene therapeutic approaches have been developed to ameliorate disease in animal models of arthritis either by restoring the cytokine balance or by genetic synovectomy. In this review we summarize strategies to improve transduction of synovial cells, to achieve stable transgene expression using integrating viruses such as adeno-associated viruses, and to achieve transcriptionally regulated expression so that drug release can meet the variable demands imposed by the intermittent course of RA. Evidence from animal models convincingly supports the application of gene therapy in RA, and the feasibility of gene therapy was recently demonstrated in phase I clinical trials.
doi:10.1186/ar1214
PMCID: PMC546285  PMID: 15380032
arthritis; cytokines; gene therapy; genetic synovectomy; transcriptional regulation
6.  Cartilage Oligomeric Matrix Protein (COMP): A Biomarker of Arthritis 
Biomarker Insights  2009;4:33-44.
Arthritis is a chronic disease with a significant impact on the population. It damages the cartilage, synovium, and bone of the joints causing pain, impairment, and disability in patients. Current methods for diagnosis of and monitoring the disease are only able to detect clinical manifestations of arthritis late in the process. However, with the recent onset of successful treatments for rheumatoid arthritis and osteoarthritis, it becomes important to identify prognostic factors that can predict the evolution of arthritis. This is especially critical in the early phases of disease so that these treatments can be started as soon as possible to slow down progression of the disease. A valuable approach to monitor arthritis would be by measuring biological markers of cartilage degradation and repair to reflect variations in joint remodeling. One such potential biological marker of arthritis is cartilage oligomeric matrix protein (COMP). In various studies, COMP has shown promise as a diagnostic and prognostic indicator and as a marker of the disease severity and the effect of treatment. This review highlights the progress in the utilization of COMP as a biomarker of arthritis.
PMCID: PMC2716683  PMID: 19652761
cartilage oligomeric matrix protein; arthritis; biomarker
7.  Clinical Responses to Gene Therapy in Joints of Two Subjects with Rheumatoid Arthritis 
Human Gene Therapy  2009;20(2):97-101.
Abstract
This paper provides the first evidence of a clinical response to gene therapy in human arthritis. Two subjects with rheumatoid arthritis received ex vivo, intraarticular delivery of human interleukin-1 receptor antagonist (IL-1Ra) cDNA. To achieve this, autologous synovial fibroblasts were transduced with a retrovirus, MFG-IRAP, carrying IL-1Ra as the transgene, or remained as untransduced controls. Symptomatic metacarpophalangeal (MCP) joints were injected with control or transduced cells. Joints were clinically evaluated on the basis of pain; the circumference of MCP joint 1 was also measured. After 4 weeks, joints underwent surgical synovectomy. There were no adverse events in either subject. The first subject responded dramatically to gene transfer, with a marked and rapid reduction in pain and swelling that lasted for the entire 4 weeks of the study. Remarkably, joints receiving IL-1Ra cDNA were protected from flares that occurred during the study period. Analysis of RNA recovered after synovectomy revealed enhanced expression of IL-1Ra and reduced expression of matrix metalloproteinase-3 and IL-1β. The second subject also responded with reduced pain and swelling. Thus, gene transfer to human, rheumatoid joints can be accomplished safely to produce clinical benefit, at least in the short term. Using this ex vivo procedure, the transgene persisted within the joint for at least 1 month. Further clinical studies are warranted.
doi:10.1089/hum.2008.075
PMCID: PMC2855248  PMID: 18986219
8.  Tissue engineering in the rheumatic diseases 
Diseases such as degenerative or rheumatoid arthritis are accompanied by joint destruction. Clinically applied tissue engineering technologies like autologous chondrocyte implantation, matrix-assisted chondrocyte implantation, or in situ recruitment of bone marrow mesenchymal stem cells target the treatment of traumatic defects or of early osteoarthritis. Inflammatory conditions in the joint hamper the application of tissue engineering during chronic joint diseases. Here, most likely, cartilage formation is impaired and engineered neocartilage will be degraded. Based on the observations that mesenchymal stem cells (a) develop into joint tissues and (b) in vitro and in vivo show immunosuppressive and anti-inflammatory qualities indicating a transplant-protecting activity, these cells are prominent candidates for future tissue engineering approaches for the treatment of rheumatic diseases. Tissue engineering also provides highly organized three-dimensional in vitro culture models of human cells and their extracellular matrix for arthritis research.
doi:10.1186/ar2572
PMCID: PMC2688224  PMID: 19232063
9.  Application of cellular gene therapy for rheumatoid arthritis 
Modern Rheumatology  2006;16(5):269-275.
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent inflammation of joints resulting in progressive destruction of cartilage and bone. Recently, biological agents that suppress the activities of proinflammatory cytokines have shown efficacy as antirheumatic drugs, but require frequent administration, and often result in systemic immune suppression. Thus, gene transfer approaches are being developed as an alternative approach for targeted, more efficient, and sustained delivery of inhibitors of inflammatory cytokines as well as other therapeutic agents. Several gene therapy approaches have been established in preclinical animal models. In these models, autoantigen-specific T cells have been demonstrated to be ideal gene delivery vehicles for the local delivery of “immunoregulatory molecules” because these cells have tissue-specific homing and retention properties. Indeed, bioluminescence studies in an animal model of inflammatory arthritis revealed that these cells accumulated in and remained in inflamed joints. Transfer of genetically modified dendritic cells (DCs) may also have interesting effects. We conclude that modifying antigen-specific T cells or autologous DCs by retroviral transduction for local expression of regulatory proteins is a promising therapeutic strategy for the treatment of RA.
doi:10.1007/s10165-006-0501-7
PMCID: PMC2780633  PMID: 17039306
Antigen-specific T cell; Cell trafficking; Dendritic cell (DC); Local delivery; Regulatory T cell
10.  Matrix metalloproteinase-8 deficiency increases joint inflammation and bone erosion in the K/BxN serum-transfer arthritis model 
Arthritis Research & Therapy  2010;12(6):R224.
Introduction
Rheumatoid arthritis is an autoimmune disease in which joint inflammation leads to progressive cartilage and bone erosion. Matrix metalloproteinases (MMPs) implicated in homeostasis of the extracellular matrix play a central role in cartilage degradation. However, the role of specific MMPs in arthritis pathogenesis is largely unknown. The aim of the present study was to investigate the role of Mmp-8 (collagenase-2) in an arthritis model.
Methods
Arthritis was induced in Mmp8-deficient and wildtype mice by K/BxN serum transfer. Arthritis severity was measured by a clinical index and ankle sections were scored for synovial inflammation, cartilage damage and bone erosion. cDNA microarray analysis, real-time PCR and western blot were performed to identify differential changes in gene expression between mice lacking Mmp8 and controls.
Results
Mmp8 deficiency increased the severity of arthritis, although the incidence of disease was similar in control and deficient mice. Increased clinical score was associated with exacerbated synovial inflammation and bone erosion. We also found that the absence of Mmp8 led to increased expression of IL-1β, pentraxin-3 (PTX3) and prokineticin receptor 2 (PROKR2) in arthritic mice joints.
Conclusions
Lack of Mmp-8 is accompanied by exacerbated synovial inflammation and bone erosion in the K/BxN serum-transfer arthritis model, indicating that this Mmp has a protective role in arthritis.
doi:10.1186/ar3211
PMCID: PMC3046537  PMID: 21190566
11.  Novel, Biocompatible, Disease Modifying Nanomedicine of VIP for Rheumatoid Arthritis 
Molecular pharmaceutics  2013;10(2):728-738.
Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nano-sized SSM-VIP but not free VIP in buffer significantly reduced incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP unlike free VIP had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA.
doi:10.1021/mp300539f
PMCID: PMC3563715  PMID: 23211088
inflammation; autoimmune disorders; phospholipids; micelles; nanomedicine; vasoactive intestinal peptide
12.  Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis 
Annals of the Rheumatic Diseases  2013;72(10):1732-1736.
Objective
To test whether inhibition of sclerostin by a targeted monoclonal antibody (Scl-Ab) protects from bone and cartilage damage in inflammatory arthritis. Sclerostin is a potent inhibitor of bone formation and may be responsible for the low level of bone repair in patients with rheumatoid arthritis.
Methods
Human tumour necrosis factor transgenic mice (hTNFtg mice) developing inflammatory arthritis and local and bone loss were administered either vehicle, anti-TNF antibody, Scl-Ab, or a combination of both agents. Inflammation, systemic and periarticular bone loss, bone erosion and cartilage damage were evaluated at baseline (week 8) and after 3 weeks of treatment by clinical assessment, micro-CT and histology.
Results
Scl-Ab did not affect joint swelling or synovitis. Systemic bone loss in the spine and periarticular bone loss in the proximal tibia were completely blocked and partially reversed by inhibition of sclerostin but not by inhibition of TNF. Moreover, Scl-Ab completely arrested the progression of bone erosion in hTNFtg mice and in combination with TNF inhibition even led to significant regression of cortical bone erosions. Protective effects of Scl-Ab were also observed for the articular cartilage.
Conclusions
These data suggest that sclerostin inhibition is a powerful tool to enhance bone repair in inflammatory arthritis.
doi:10.1136/annrheumdis-2013-203345
PMCID: PMC3786639  PMID: 23666928
Anti-TNF; Rheumatoid Arthritis; Inflammation; Bone Mineral Density
13.  Reduction of CXCR4 expression in Rheumatoid Arthritis Rat Joints by low level diode laser irradiation 
Laser Therapy  2011;20(1):53-58.
Background: Rheumatoid arthritis (RA) is an inflammatory joint disorder, whose progression leads to the destruction of cartilage and bone. Chemokines and their receptors are potential therapeutic targets in RA. Among these, it has been suggested that CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (CXCL12) are involved in RA pathogenesis. Low-level laser irradiation (LLLI) is currently being evaluated for the treatment of RA; however, the molecular mechanisms underlying its effectiveness remain unclear.
Aim: To understand the anti-inflammatory effect of LLLI, we used the collagen-induced arthritis (CIA) rat as RA model and analyzed the gene expression profile in synovial membrane in the hindpaw joints of control, CIA and CIA + LLLI. Expression of CXCR4 and CXCL12 genes were also studied.
Materials and Methods: Total RNA was isolated from the synovial membrane tissue of CIA rat joints or CIA joints treated with LLLI (830 nm Ga-Al-As diode), and gene expression profiles were analyzed by DNA microarray (41,000 rat genes). The mRNA levels were confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR. Immunohistochemical examination to examine CXCR4 protein expression was also carried out.
Results: DNA microarray analysis showed that CXCR4 gene expression was increased in CIA tissue and LLLI treatment significantly decreased CIA-induced CXCR4 mRNA levels. In contrast, CXCL12 did not show any significant changes. The microarray data of CXCR4 mRNA levels were further validated using RT-PCR and real-time PCR. Increased CXCR4 mRNA levels by CIA and its reduction following LLLI was successfully confirmed. CXCR4 production was increased in CIA joints and its production was decreased by LLLI.
Conclusion: Decreased CXCR4 expression may be one of the mechanisms in LLLI-mediated reduction of RA inflammation.
doi:10.5978/islsm.20.53
PMCID: PMC3806082  PMID: 24155514
Rheumatoid arthritis; rat joint; CXCR4; low-level laser irradiation
14.  Chinese Herbal Formula Huo-Luo-Xiao-Ling Dan Protects against Bone Damage in Adjuvant Arthritis by Modulating the Mediators of Bone Remodeling 
Huo-luo-xiao-ling dan (HLXL) is an herbal mixture that has long been used in traditional Chinese medicine for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Despite the availability of potent conventionally used drugs for RA, their limited efficacy in a proportion of patients coupled with their high cost and severe adverse effects has necessitated the search for novel therapeutics for this debilitating disease. Further, the control of both inflammation and bone damage is essential for effective management of arthritis. The aim of our study was to evaluate the efficacy of HLXL against arthritic bone damage in adjuvant arthritis (AA) model of RA. Our results show that HLXL treatment suppressed inflammatory arthritis and reduced bone and cartilage damage in the joints of arthritic Lewis rats. HLXL-induced protection against bone damage was mediated primarily via inhibition of mediators of osteoclastic bone remodeling (e.g., receptor activator of nuclear factor kappa-B ligand; RANKL), skewing of RANKL/osteoprotegerin (OPG) ratio in favor of antiosteoclastic activity, reduction in the number of osteoclasts in the arthrodial joint's bone, and inhibition of cytokine production and MMP activity. Our results suggest that HLXL might offer a promising alternative/adjunct treatment for both inflammation and bone damage in RA.
doi:10.1155/2013/429606
PMCID: PMC3670518  PMID: 23762133
15.  Loss of MMP-2 disrupts skeletal and craniofacial development, and results in decreased bone mineralization, joint erosion, and defects in osteoblast and osteoclast growth 
Human molecular genetics  2007;16(9):1113-1123.
The “vanishing bone” or inherited osteolysis/arthritis syndromes represent a heterogeneous group of skeletal disorders characterized by mineralization defects of affected bones and joints. Differing in anatomical distribution, severity, and associated syndromic features, gene identification in each “vanishing bone” disorder should provide unique insights into genetic/molecular pathways contributing to the overall control of skeletal growth and development. We previously described and then demonstrated that the novel autosomal recessive osteolysis/arthritis syndrome, Multicentric Osteolysis with Arthritis (MOA [MIM #605156]), was caused by inactivating mutations in the MMP2 gene (1). These in vivo results were counterintuitive and unexpected since previous in vitro studies suggested that MMP-2 overexpression and increased activity, not deficiency, would result in the bone and joint features of MOA. The apparent lack of a murine model (2) has hindered studies on disease pathogenesis and, more fundamentally, in addressing the paradox of how functional loss of a single proteolytic enzyme results in an apparent increase in bone loss. Here, we report that Mmp2-/- mice display attenuated features of human MOA including progressive loss of bone mineral density, articular cartilage destruction, and abnormal long bone and craniofacial development. Moreover, these changes are associated with markedly and developmentally-restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2-/- mice have ∼50% fewer osteoblasts and osteoclasts than control littermates at 4 days of life but these differences have nearly resolved by 4 weeks of age. In addition, despite normal cell numbers in vivo at 8 weeks of life, Mmp2-/- bone marrow cells are unable to effectively support osteoblast and osteoclast growth and differentiation in culture. Targeted inhibition of MMP-2 using siRNA in human SaOS2 and murine MC3T3 osteoblast cell lines resulted in decreased cell proliferation rates. Taken together, our findings suggest that MMP-2 plays a direct role in early skeletal development and bone cell growth and proliferation. Thus, Mmp2-/- mice provide a valuable biologic resource for studying the pathophysiologic mechanisms underlying the human disease and defining the in vivo physiologic role of MMP-2.
doi:10.1093/hmg/ddm060
PMCID: PMC2576517  PMID: 17400654
16.  Perspectives for TNF-α-targeting therapies 
Arthritis Research  2002;4(Suppl 3):S17-S24.
Chapter summary
Rheumatoid arthritis (RA) is the most common chronic autoimmunopathy, clinically leading to joint destruction as a consequence of the chronic inflammatory processes. The pathogenesis of this disabling disease is not well understood, but molecular events leading to tissue inflammation with cartilage and bone destruction are now better defined. Therapy with slow-acting, disease-modifying antirheumatic drugs (DMARDs), such as low-dose methotrexate, which is generally accepted as a standard, leads to a significant amelioration of symptoms but does not stop joint destruction. Due to these disappointing treatment options and the identification of certain inflammatory mediators as therapeutic targets, novel therapeutic agents such as monoclonal antibodies, cytokine-receptor/human-immunoglobulin constructs or recombinant human proteins have been tested in RA with some success. Clinical trials testing anti-TNF-α agents, alone or in combination with methotrexate, have convincingly shown the feasibility and efficacy of these novel approaches to the therapy of RA. A clinical trial testing combination therapy with chimeric (mouse/human) anti-TNF-α monoclonal antibody infliximab and methotrexate showed, for the first time in any RA trial, that there was no median radiological progression in the groups given infliximab plus methotrexate over a 12-month observation period. Similar encouraging results might arise from trials employing other TNF-α-directed agents, such as the fully human monoclonal antibody D2E7, the p75 TNF-α-receptor/Ig construct, etanercept, or others, as discussed in this review. Combination partners other than methotrexate will be established as suitable cotreatment along with anti-TNF-α biologicals. Forthcoming new indications for TNF-α-targeted therapies are discussed.
doi:10.1186/ar564
PMCID: PMC3240140  PMID: 12110119
D2E7; etanercept; infliximab; TNF-α; therapy
17.  Therapeutic Effect of a Poly(ADP-Ribose) Polymerase-1 Inhibitor on Experimental Arthritis by Downregulating Inflammation and Th1 Response 
PLoS ONE  2007;2(10):e1071.
Poly(ADP-ribose) polymerase-1 (PARP-1) synthesizes and transfers ADP ribose polymers to target proteins, and regulates DNA repair and genomic integrity maintenance. PARP-1 also plays a crucial role in the progression of the inflammatory response, and its inhibition confers protection in several models of inflammatory disorders. Here, we investigate the impact of a selective PARP-1 inhibitor in experimental arthritis. PARP-1 inhibition with 5-aminoisoquinolinone (AIQ) significantly reduces incidence and severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of AIQ is associated with a striking reduction of the two deleterious components of the disease, i.e. the Th1-driven autoimmune and inflammatory responses. AIQ downregulates the production of various inflammatory cytokines and chemokines, decreases the antigen-specific Th1-cell expansion, and induces the production of the anti-inflammatory cytokine IL-10. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein as a potential therapeutic target for the treatment of rheumatoid arthritis.
doi:10.1371/journal.pone.0001071
PMCID: PMC2034533  PMID: 17971849
18.  Musings on genome medicine: gene therapy 
Genome Medicine  2009;1(4):38.
Though the field has moved with glacial speed, gene therapies have been carried out successfully in patients with bone marrow disorders including immune deficiencies. The field may be poised to move forward more rapidly, but many barriers have yet to be surmounted.
doi:10.1186/gm38
PMCID: PMC2684659  PMID: 19435468
19.  The angiogenesis inhibitor protease-activated kringles 1–5 reduces the severity of murine collagen-induced arthritis 
Arthritis Research & Therapy  2002;5(1):R32-R39.
During rheumatoid arthritis there is enlargement and increased cellularity of the synovial lining of joints, before invasion by the synovium of the underlying cartilage and bone. This increased tissue mass requires a network of blood vessels to supply nutrients and oxygen. Disruption of synovial angiogenesis is thus a desirable aim of antiarthritic therapies. Protease-activated kringles 1–5 (K1–5) is an angiogenesis inhibitor related to angiostatin. In common with angiostatin, K1–5 contains the first four kringle domains of plasminogen, but also encompasses the kringle 5 domain, which confers enhanced antiangiogenic activity when compared with angiostatin. The purpose of the present study was to assess the effect on murine arthritis of K1–5. Arthritis was induced in DBA/1 mice by a single injection of bovine collagen. Treatment with K1–5 was commenced on the day of arthritis onset and continued for 10 days, until the end of the experiment. Daily intraperitoneal administration of K1–5 (2 mg/kg body weight) significantly reduced both paw swelling and clinical score (a composite index of the number of arthritic limbs and the severity of disease). The clinical efficacy of this treatment was reflected by a reduction in joint inflammation and destruction, as assessed histologically. These data suggest that antiangiogenic therapies, which block formation of new blood vessels and hence reduce synovial expansion, might be effective in treating rheumatoid arthritis.
doi:10.1186/ar608
PMCID: PMC154428  PMID: 12716451
angiogenesis; arthritis
20.  Orthopaedic applications of gene therapy 
International Orthopaedics  2005;29(4):205-209.
Gene therapy presents a novel approach to biological treatment. Several orthopaedic diseases can cause changes in biological signalling at the tissue level that potentially can be repaired or modified by inserting genes into the cells or tissues to modulate gene expression. Impaired bone healing, need for extensive bone formation, cartilage repair and metabolic bone diseases are all conditions where alterations of the signalling peptides involved may provide cure or improvement. In orthopaedic oncology, gene therapy may achieve induction of tumour necrosis and increased tumour sensitivity to chemotherapy. In the last decade, extensive improvements have been made to optimise gene therapy and have been tested on several orthopaedic conditions. How far this development has come in orthopaedics is highlighted in this paper.
doi:10.1007/s00264-005-0650-x
PMCID: PMC3474530  PMID: 15900437
21.  The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics 
Arthritis Research & Therapy  2005;7(6):273-278.
The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics was held in Boston, Massachusetts, USA in May 2004. Keystone lectures delivered by Drs Joseph Glorioso and Inder Verma provided comprehensive, up-to-date information on all major virus vectors. Other invited speakers covered the application of gene therapy to treatment of arthritis, including the latest clinical trial in rheumatoid arthritis, as well as lupus and Sjögren's syndrome. Applications in mesenchymal stem cell biology, tissue repair, and regenerative medicine were also addressed. The field has advanced considerably since the previous meeting in this series, and further clinical trials seem likely.
doi:10.1186/ar1853
PMCID: PMC1297596  PMID: 16277703
22.  Musculoskeletal molecular imaging: a comprehensive overview 
Trends in biotechnology  2010;28(2):93-101.
Molecular imaging permits non-invasive visualization and measurement of molecular and cell biology in living subjects, thereby complementing conventional anatomical imaging. Herein, we review the emerging application of molecular imaging for the study of musculoskeletal biology. Utilizing mainly bioluminescence and fluorescence techniques, molecular imaging has enabled in-vivo studies of (i) the activity of osteoblasts, osteoclasts, and hormones, (ii) the mechanisms of pathological cartilage and bone destruction, (iii) skeletal gene and cell therapy with and without biomaterial support, and (iv) the cellular processes in osteolysis and osteomyelitis. In these applications, musculoskeletal molecular imaging demonstrated feasibility for research in a myriad of musculoskeletal conditions ranging from bone fracture and arthritis to skeletal cancer. Importantly, these advances herald great potential for innovative clinical imaging in orthopedics, rheumatology, and oncology.
doi:10.1016/j.tibtech.2009.11.004
PMCID: PMC3017378  PMID: 20045210
23.  Dynamic activation of bone morphogenetic protein signaling in collagen-induced arthritis supports their role in joint homeostasis and disease 
Arthritis Research & Therapy  2008;10(5):R115.
Introduction
Rheumatoid arthritis is a chronic systemic autoimmune disease affecting peripheral joints and leading to loss of joint function. The severity and outcome of disease are dependent on the balance between inflammatory/destructive and homeostatic or repair pathways. Increasing evidence suggests a role for bone morphogenetic protein (BMP) signaling in joint homeostasis and disease.
Methods
Activation of BMP signaling in collagen-induced arthritis as a model of rheumatoid arthritis was studied by immunohistochemistry and Western blot for phosphorylated SMAD1/5 at different time points. Expression of different BMP ligands and noggin, a BMP antagonist, was determined on synovium and cartilage extracts of arthritic knees, at different time points, with quantitative polymerase chain reaction. At the protein level, BMP2 and BMP7 were studied with immunohistochemistry. Finally, the effect of anti-tumor necrosis factor-alpha (TNFα) treatment on the expression of BMP2, BMP7, and growth and differentiation factor-5 (GDF5) in synovium and cartilage of arthritic knees was investigated.
Results
A time-dependent activation of the BMP signaling pathway in collagen-induced arthritis was demonstrated with a dynamic and characteristic expression pattern of different BMP subfamily members in synovium and cartilage of arthritic knees. As severity increases, the activation of BMP signaling becomes more prominent in the invasive pannus tissue. BMP2 is present in cartilage and the hyperplastic lining layer. BMP7 is found in the sublining zone and inflammatory infiltrate. Treatment with etanercept slowed down progression of disease, but no change in expression of GDF5, BMP2, and BMP7 in synovium was found; in the cartilage, however, blocking of TNFα increased the expression of BMP7.
Conclusions
BMP signaling is dynamically activated in collagen-induced arthritis and is partly TNFα-independent. TNFα blocking increased the expression of BMP7 in the articular cartilage, possibly enhancing anabolic mechanisms. Different types of source and target cells are recognized. These data further support a role for BMP signaling in arthritis.
doi:10.1186/ar2518
PMCID: PMC2592802  PMID: 18816401
24.  C17 Prevents Inflammatory Arthritis and Associated Joint Destruction in Mice 
PLoS ONE  2011;6(7):e22256.
C17 was first described about ten years ago as a gene expressed in CD34+ cells. A more recent study has suggested a role for C17 in chondrogenesis and development of cartilage. However, based on sequence analysis, we believe that C17 has homology to IL-2 and hence we present the hypothesis that C17 is a cytokine possessing immune-regulatory properties. We provide evidence that C17 is a secreted protein preferentially expressed in chondrocytes, hence in cartilage-rich tissues. Systemic expression of C17 in vivo reduces disease in a collagen antibody-induced arthritis model in mice (CAIA). Joint protection is evident by delayed disease onset, minimal edema, bone protection and absence of diverse histological features of disease. Expression of genes typically associated with acute joint inflammation and erosion of cartilage or bone is blunted in the presence of C17. Consistent with the observed reduction in bone erosion, we demonstrate reduced levels of RANKL in the paws and sera of mice over-expressing C17. Administration of C17 at the peak of disease, however, had no effect on disease progression, indicating that C17's immune-regulatory activity must be most prominent prior to or at the onset of severe joint inflammation. Based on this data we propose C17 as a cytokine that s contributes to immune homeostasis systemically or in a tissue-specific manner in the joint.
doi:10.1371/journal.pone.0022256
PMCID: PMC3143151  PMID: 21799806
25.  Differences in MRI findings between subgroups of recent-onset childhood arthritis 
Pediatric Radiology  2010;41(4):432-440.
Background
MRI is sensitive for joint inflammation, but its ability to separate subgroups of arthritis in children has been questioned. Infectious arthritis (IA), postinfectious arthritis (PA), transient arthritis (TA) and juvenile idiopathic arthritis (JIA) are subgroups that may need early, different treatment.
Objective
To determine whether MRI findings differ in IA, PA/TA and JIA in recent-onset childhood arthritis.
Materials and methods
Fifty-nine children from a prospective study of incidence of arthritis (n = 216) were, based on clinical and biochemical criteria, examined by MRI. Joint fluid, synovium, bone marrow, soft tissue and cartilage were scored retrospectively and analysed by Pearson chi-square test and logistic regression analysis.
Results
Fifty-nine children had MRI of one station. IA was suggested by bone marrow oedema (OR 7.46, P = 0.011) and absence of T1-weighted and T2-weighted low signal intensity synovial tissue (OR 0.06, P = 0.015). Furthermore, soft-tissue oedema and reduced contrast enhancement in the epiphyses were more frequent in children with IA. JIA correlated positively with low signal intensity synovial tissue (OR 13.30, P < 0.001) and negatively with soft-tissue oedema (OR 0.20, P = 0.018). No significant positive determinants were found for PA/TA, but bone marrow oedema, soft-tissue oedema, irregular thickened synovium and low signal intensity synovial tissue was less frequent than in IA/JIA.
Conclusion
In children with high clinical suspicion of recent onset arthritis, there was a significant difference in the distribution of specific MRI features among the diagnostic groups.
doi:10.1007/s00247-010-1897-y
PMCID: PMC3063538  PMID: 21136049
Septic arthritis; Juvenile idiopathic arthritis; MRI; Child; Transient arthritis

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