Abstract
Angiogenesis plays a crucial role in the pathogenesis of inflammatory diseases, including rheumatoid arthritis (RA). Therefore, targeting neovascularization in RA may hold great therapeutic potential. Several mediating factors are involved in synovial angiogenesis, including growth factors, cytokines, chemokines, adhesion molecules, and matrix-remodeling enzymes. This review aims to summarize the current understanding of these contributing factors in RA, as well as to describe both the preclinical and clinical studies in which these factors are targeted in an attempt to ameliorate the symptoms associated with RA. In addition, we highlight methods to monitor synovial angiogenesis in patients and discuss possible future therapeutic approaches in RA, including the combination of existing immunosuppressive antirheumatic therapies and anti-angiogenic treatments to potentially maximize efficacy with limited toxicity.
Angiogenesis
Angiogenesis is a vital biological process, forming new capillaries from preexisting blood vessels and infusing tissue with supplies of oxygen and nutrients. It plays an important role in physiological conditions such as reproduction, development, wound healing, and tissue repair. Accumulating evidence also demonstrates that aberrant angiogenesis is a crucial mediator in a growing list of diseases such as cancer, chronic inflammatory diseases, atherosclerosis, and diabetic retinopathy, making substantial contributions to disease pathogenesis. Thus, studying the mechanisms that regulate angiogenesis holds vast therapeutic potential in alleviating or halting disease progression in such diseases .
The process of angiogenesis is complex, consisting of tightly regulated steps and the involvement of several cell types interacting with each other as well as with the surrounding microenvironment. Angiogenesis is generally induced by hypoxia, leading to the upregulation of pro-angiogenic factors, most notably vascular endothelial growth factor (VEGF), that activate the endothelial cells (ECs) of the preexisting vasculature to sprout and increase vascularization of the tissue. Vessel sprouting relies on a migrating endothelial “tip” cell that guides the vessel and endothelial “stalk” cells that elongate the sprouting vessel via proliferation. VEGF is a tip cell signal, whereas delta-like 4 (DLL4)/Notch signaling is a stalk cell signal. Subsequently, these cells start to migrate in the direction of the hypoxic tissue, following a gradient of VEGF, while simultaneously proliferating and attracting endothelial progenitor cells (EPCs) to make up the inner layer of the newly formed vasculature. In order to construct vessels within the preexisting tissue architecture, degradation of the extracellular matrix (ECM) must also occur and this is done mainly through the actions of matrix-remodeling enzymes such as matrix metalloproteinases (MMPs). Once the vasculature has extended into the hypoxic region, maturation begins with pericytes localizing to the nascent blood vessels and forming an outer layer around the ECs. Next, ECs form tighter junctions through adhesion molecules, followed by deposition of a basement membrane. Finally, the vessel is mature and ready for perfusion of the hypoxic tissue .
Several mediators are involved in this highly orchestrated process, creating a fine balance between angiogenic and angiostatic signals that support the ultimate goal of mature vessel formation and perfusion. Besides VEGF, other growth factors such as placental growth factor (PlGF), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGFβ) contribute to this process. Cytokines and chemokines have a dual role in this process. The cytokines tumor necrosis factor alpha (TNFα), interleukin (IL)-1, IL-6, IL-8, IL-15, IL-17, IL-18, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and oncostatin M, and the chemokines C–C motif ligand (CCL)-2, C–X–C motif ligand (CXCL)-5, CXCL1, CXCL6, CXCL12, and macrophage migratory inhibitory factor (MIF) are known stimulators of angiogenesis , whereas interferon gamma (IFNγ), interferon alpha (IFNα), IL-4, IL-12, IL-13, CXCL4, CXCL9, CXCL10, and CCL21 may have inhibitory functions 7. Importantly, adhesion molecules (α v β 3 , E-selectin, vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 2 (ICAM-2), and platelet/endothelial cell adhesion molecule 1 (PECAM-1)) and MMPs (MMP1, MMP2, MMP3, and MMP9) also contribute to effective angiogenic responses. The key signaling molecules that are involved in angiogenesis include angiopoietins (Ang-1 and Ang-2), intermediates of Notch signaling, and members of the nuclear factor (NF)-κB family of transcription factors, including upstream activating kinases . Under normal physiological circumstances, the balance between angiogenic and angiostatic signals is maintained. However, under pathological conditions such as tumor growth or chronic inflammation, the balance is tipped towards a pro-angiogenic phenotype and angiogenesis occurs continuously with a lack of resolution. This is, for a large part, due to immune cells and the factors that they produce.
Angiogenesis in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the infiltration of immune cells into the synovial joint, in conjunction with an increase of the synovial lining layer leading to pannus formation and subsequent cartilage and bone destruction of the joint . Angiogenesis has been identified as an important marker of disease progression in RA and is often regarded as a “switch” from acute to chronic inflammation . This is due to the capacity of angiogenesis not only to sustain the expanding cell populations within the synovial joint by increasing oxygen and nutrient availability but also to further enhance leukocyte recruitment into the tissues . In addition, it contributes to the bone and cartilage destruction associated with the disease .
As alluded to earlier, one of the main drivers of angiogenesis is hypoxia, which has been described in several types of arthritis, including RA. Interestingly, synovial oxygen tension in RA is inversely correlated with the inflammatory cell markers CD3 (T cells) and CD68 (macrophages) . Hypoxic conditions lead to the translation of hypoxia-inducible factor 1 alpha (HIF1α) protein, followed by active gene transcription of the HIF-responsive genes, including VEGF. HIF1α is highly expressed in the sublining layer of RA synovial tissue and at significantly higher levels in tissue of RA patients as compared to osteoarthritis (OA) patients. It was also observed that the levels of HIF1α correlate strongly with the number of blood vessels, EC proliferation, and synovitis scores in RA . This is in line with other studies showing a clear association between VEGF levels and disease activity in RA .
Various cell types in the inflamed synovium produce pro-angiogenic factors, as illustrated in Fig. 1 . RA fibroblast-like synoviocytes (FLS), for instance, are major contributors to angiogenesis in RA, as they express a wide array of growth factors, cytokines, chemokines, adhesion molecules, and matrix-remodeling enzymes, including VEGF, bFGF, TGFβ IL-6, IL-8, CXCL12, ICAM-1, VCAM-1, and MMP1, MMP2, MMP3, and MMP9 . Another major source of pro-angiogenic molecules are macrophages, which are either an integrative part of the synovial lining layer or localized to the tissue and differentiated from monocyte precursor cells. In RA, macrophages can produce an eclectic variety of mediators, including growth factors (i.e., VEGF, basic FGF, PDGF, HGF, and TGFβ), cytokines (i.e., TNFα, IL-1, IL-6, IL-8, GM-CSF, and oncostatin M), chemokines (i.e., CCL2, CXCL1, and CXCL5), and matrix-remodeling enzymes (i.e., MMP1, MMP2, and MMP9) . A subset of macrophages expressing Tie-2 is currently under intense investigation for their role in synovial angiogenesis as the Ang/Tie-2 system is important for angiogenesis . T cells are also thought to contribute to synovial angiogenesis through the production of VEGF and by stimulation of FLS and macrophages through CD40L, which induces the expression of several pro-angiogenic molecules . T cells and B cells that are present in the inflamed synovial tissue also produce lymphotoxin β (LTβ) and LIGHT (homologous to Lymphotoxins, exhibits Inducible expression, and competes with herpes simplex virus (HSV) Glycoprotein D for Herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) , both ligands of the LTβR, which can either directly or via stimulation of other cells induce angiogenesis . T helper 17 (Th17) cells play an important role in RA pathogenesis, and accumulating evidence demonstrates that IL-17A has a pro-angiogenic effect in the synovium . IL-17A was demonstrated to induce EC migration as well as tube formation and blood vessel formation in Matrigel plugs. Moreover, the local expression of IL-17A in mouse ankle joints led to a clear increase in vascularity . IL-17-positive mast cells accumulate in many tissues that are characterized by angiogenesis, including RA synovial tissue. Mast cells are the main IL-17-positive cells in anti-citrullinated protein antibody-positive and antibody-negative RA synovium , and mast cells produce several pro-angiogenic mediators that regulate both EC proliferation and function . This is illustrated by the fact that mast cell-deficient Kit W / Kit W − v mice are resistant to antibody-induced arthritis. Interestingly, intra-articular and intraperitoneal mast cell engraftment fully restored susceptibility to arthritis, angiogenesis, and α v β 3 integrin activation in these mice .
With the abundance of pro-angiogenic factors in the RA synovial joint, it is clear why one of the hallmarks of RA is neovascularization. However, an increase in blood vessels is not necessarily always associated with an improved perfusion of the tissue. This may be attributed to the lack of maturation of the newly formed vessels along with an irregular morphology, hence creating a paradox of increased synovial blood vessel density with a continued state of hypoxia . Nevertheless, angiogenesis undoubtedly contributes to the persistence of inflammation, not in the least via the continuous attraction of immune cells to the inflamed synovial tissue.
Angiogenesis plays a crucial role in the pathogenesis of RA by supporting expanding cell populations in the inflamed synovium with nutrients and oxygen, as well as contributing to immune cell infiltration
- •
Arthroscopic evaluation reveals neovascularization of the synovial tissue in RA patients
- •
Hypoxia, expression of the key pro-angiogenic growth factor VEGF and synovial blood vessel formation is positively correlated with disease activity
- •
Synovial angiogenesis is driven not only by hypoxia but also by inflammatory mediators produced by stromal cells and infiltrating immune cells
Angiogenesis in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the infiltration of immune cells into the synovial joint, in conjunction with an increase of the synovial lining layer leading to pannus formation and subsequent cartilage and bone destruction of the joint . Angiogenesis has been identified as an important marker of disease progression in RA and is often regarded as a “switch” from acute to chronic inflammation . This is due to the capacity of angiogenesis not only to sustain the expanding cell populations within the synovial joint by increasing oxygen and nutrient availability but also to further enhance leukocyte recruitment into the tissues . In addition, it contributes to the bone and cartilage destruction associated with the disease .
As alluded to earlier, one of the main drivers of angiogenesis is hypoxia, which has been described in several types of arthritis, including RA. Interestingly, synovial oxygen tension in RA is inversely correlated with the inflammatory cell markers CD3 (T cells) and CD68 (macrophages) . Hypoxic conditions lead to the translation of hypoxia-inducible factor 1 alpha (HIF1α) protein, followed by active gene transcription of the HIF-responsive genes, including VEGF. HIF1α is highly expressed in the sublining layer of RA synovial tissue and at significantly higher levels in tissue of RA patients as compared to osteoarthritis (OA) patients. It was also observed that the levels of HIF1α correlate strongly with the number of blood vessels, EC proliferation, and synovitis scores in RA . This is in line with other studies showing a clear association between VEGF levels and disease activity in RA .
Various cell types in the inflamed synovium produce pro-angiogenic factors, as illustrated in Fig. 1 . RA fibroblast-like synoviocytes (FLS), for instance, are major contributors to angiogenesis in RA, as they express a wide array of growth factors, cytokines, chemokines, adhesion molecules, and matrix-remodeling enzymes, including VEGF, bFGF, TGFβ IL-6, IL-8, CXCL12, ICAM-1, VCAM-1, and MMP1, MMP2, MMP3, and MMP9 . Another major source of pro-angiogenic molecules are macrophages, which are either an integrative part of the synovial lining layer or localized to the tissue and differentiated from monocyte precursor cells. In RA, macrophages can produce an eclectic variety of mediators, including growth factors (i.e., VEGF, basic FGF, PDGF, HGF, and TGFβ), cytokines (i.e., TNFα, IL-1, IL-6, IL-8, GM-CSF, and oncostatin M), chemokines (i.e., CCL2, CXCL1, and CXCL5), and matrix-remodeling enzymes (i.e., MMP1, MMP2, and MMP9) . A subset of macrophages expressing Tie-2 is currently under intense investigation for their role in synovial angiogenesis as the Ang/Tie-2 system is important for angiogenesis . T cells are also thought to contribute to synovial angiogenesis through the production of VEGF and by stimulation of FLS and macrophages through CD40L, which induces the expression of several pro-angiogenic molecules . T cells and B cells that are present in the inflamed synovial tissue also produce lymphotoxin β (LTβ) and LIGHT (homologous to Lymphotoxins, exhibits Inducible expression, and competes with herpes simplex virus (HSV) Glycoprotein D for Herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) , both ligands of the LTβR, which can either directly or via stimulation of other cells induce angiogenesis . T helper 17 (Th17) cells play an important role in RA pathogenesis, and accumulating evidence demonstrates that IL-17A has a pro-angiogenic effect in the synovium . IL-17A was demonstrated to induce EC migration as well as tube formation and blood vessel formation in Matrigel plugs. Moreover, the local expression of IL-17A in mouse ankle joints led to a clear increase in vascularity . IL-17-positive mast cells accumulate in many tissues that are characterized by angiogenesis, including RA synovial tissue. Mast cells are the main IL-17-positive cells in anti-citrullinated protein antibody-positive and antibody-negative RA synovium , and mast cells produce several pro-angiogenic mediators that regulate both EC proliferation and function . This is illustrated by the fact that mast cell-deficient Kit W / Kit W − v mice are resistant to antibody-induced arthritis. Interestingly, intra-articular and intraperitoneal mast cell engraftment fully restored susceptibility to arthritis, angiogenesis, and α v β 3 integrin activation in these mice .
With the abundance of pro-angiogenic factors in the RA synovial joint, it is clear why one of the hallmarks of RA is neovascularization. However, an increase in blood vessels is not necessarily always associated with an improved perfusion of the tissue. This may be attributed to the lack of maturation of the newly formed vessels along with an irregular morphology, hence creating a paradox of increased synovial blood vessel density with a continued state of hypoxia . Nevertheless, angiogenesis undoubtedly contributes to the persistence of inflammation, not in the least via the continuous attraction of immune cells to the inflamed synovial tissue.
Angiogenesis plays a crucial role in the pathogenesis of RA by supporting expanding cell populations in the inflamed synovium with nutrients and oxygen, as well as contributing to immune cell infiltration
- •
Arthroscopic evaluation reveals neovascularization of the synovial tissue in RA patients
- •
Hypoxia, expression of the key pro-angiogenic growth factor VEGF and synovial blood vessel formation is positively correlated with disease activity
- •
Synovial angiogenesis is driven not only by hypoxia but also by inflammatory mediators produced by stromal cells and infiltrating immune cells
Targeting angiogenesis in RA
Mounting evidence demonstrates that angiogenesis is a crucial mediator in RA disease progression. Therefore, targeting angiogenesis in RA may be of great therapeutic value. While several therapeutics have been developed to target angiogenesis, especially in the field of oncology, it is still widely unknown what their efficacy would be in the reduction of signs and symptoms in RA.
VEGF signaling
The VEGF pathway has been extensively targeted with the development of monoclonal antibodies that neutralize VEGF (bevacizumab), soluble VEGF receptors (VEGFRs), antisense VEGF complementary DNA (cDNA), as well as inhibitory molecules that block VEGF signaling, including tyrosine kinase inhibitors (TKIs) such as sunitinib and sorafenib. These have been tested predominantly in cancer and show clear efficacy. Hence, they are currently widely used in the field of clinical oncology . The high VEGF levels in RA have fostered the notion that targeting this pathway may also be beneficial in treating RA. Initial studies in the collagen-induced arthritis (CIA) mouse model indeed showed that administration of an anti-VEGF serum before the onset of arthritis could delay disease onset as well as reduce disease severity and significantly decrease the number of blood vessels. However, if treatment was commenced after the onset of disease, no clear effect on disease incidence or severity was observed, suggesting that VEGF plays an important role during the earliest phase of arthritis and targeting this pathway is probably most effective early in the course of disease . Interestingly, targeting of VEGFR1, but not VEGFR2, through the use of blocking antibodies was also able to reduce bone and cartilage destruction, as well as disease severity in both CIA and the spontaneous K/BxN arthritis mouse model . Soluble VEGFR1 administration has also been demonstrated to significantly decrease symptoms associated with established arthritis .
More recent studies indicate that the compound norisoboldine (NOR) is able to limit angiogenesis through the inhibition of VEGF-induced mobilization of ECs . Administration of NOR in the adjuvant-induced arthritis (AIA) rat model caused a significant reduction in the number of blood vessels and a decrease in the expression of growth factors in the synovium. This reduction by NOR was probably achieved through interference of the Notch1 signaling pathway, thereby preventing the endothelial tip cell phenotype, which is a crucial initiator of the angiogenic process . Another possible method of targeting VEGF production is through the use of endogenous inhibitors of angiogenesis such as endostatin. In rat adjuvant arthritis (AA), application of recombinant human (rh) endostatin led to a decrease in VEGF expression in both the cartilage and synovial tissue, which was accompanied by an attenuation of paw swelling and a reduction in new blood vessel formation . Additional studies also confirmed that administration of rhEndostatin in the AA rat model lead to downregulation of VEGF as well as suppression of the inflammatory cytokines TNFα and IL-1β, resulting in a reduction of arthritis severity . These studies indicate that endostatin can act as an inhibitor of VEGF production, which may be useful in the treatment of RA. Nevertheless, to date, VEGF inhibition has not entered clinical trials for RA yet.
Integrins
Integrins are also known to play a key role in angiogenesis; thus, therapies targeting these molecules are under intense investigation as possible inhibitors of synovial angiogenesis. One example is the targeted inhibition of the integrin α v β 3 , a central molecule in EC activation and blood vessel formation . A relatively straightforward method to target α v β 3 -expressing blood vessels is via the induction of apoptosis in the synovial neovasculature using an arginine–glycine–aspartate (RGD)-containing cyclic peptide that binds selectively to α v β 3 and α v β 5 integrins. This approach was effective in ameliorating arthritis in the CIA model . Vitaxin (also known as MEDI-522) is a humanized monoclonal IgG1 antibody that specifically binds to α v β 3 and blocks the interactions between α v β 3 and several components of the ECM. In animal studies of arthritis, Vitaxin was able to inhibit synovial angiogenesis . This led to a phase II clinical trial for RA; however, its efficacy was limited . Mast cells are known to play a role in α v β 3 activation in the glucose-6-phosphate isomerase (GPI)-antibody-induced arthritis model. Kneilling et al. demonstrated that selective targeting of mast cells through salbutamol or cromolyn prevented α v β 3 activation, angiogenesis, and joint destruction . Other methods targeting α v β 3 integrin signaling in angiogenesis such as a cyclic peptide α v β 3 antagonist (Cilengitide) and small interfering RNA (siRNA) are currently under investigation for their possible therapeutic potential in oncology and may also prove beneficial in the treatment of RA .
HIF-1α
Targeting the HIF-1α pathway may have the potential to block angiogenesis in RA. However, to date, mainly indirect beneficial effects of targeting this pathway in non-EC stromal cells and immune cells have been described. In a CIA model in mice selectively deficient for HIF-1α in macrophages, the severity of arthritis was reduced as characterized by a reduction in paw swelling and disease development . In an in vivo model, in which Matrigel plugs containing human RA FLS were transplanted into immunodeficient mice causing an increase in myeloid cell infiltration and angiogenesis in the implants, targeting of the HIF pathway using siRNA or pretreatment of FLS with a transcriptional inhibitor of HIF (chetomin) led to a decrease in both HIF and VEGF messenger RNA (mRNA) levels and a significant decrease in cell infiltration and blood vessel formation . Interestingly, inhibition of histone deactylase with FK228 also results in a decrease in HIF-1α and VEGF on mRNA and protein levels. Intravenous administration of FK228 (2.5 mg/kg) in an antibody-induced murine arthritis model suppressed VEGF expression and blocked angiogenesis in the synovial tissues . In line with this, BP-1, a molecule that inhibits HIF-1α function, ameliorated arthritis as well as inhibited VEGF production and neovascularization in the AIA rat model . These studies clearly support the idea that targeting HIF-1α may have therapeutic potential in RA. Although the application of these therapeutics in human clinical trials of RA has yet to be investigated, an initial pilot trial of an HIF-1α inhibitor used in the treatment of advanced solid tumors showed promise, as both HIF-1α and VEGF levels strongly decreased along with a decrease in tumor blood flow and vessel permeability in vivo assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) .
Cytokines
Current therapeutic strategies in RA and other chronic inflammatory diseases include the blockade of TNFα-, IL-6-, or IL-1β-induced cytokine signaling. Such therapies include TNFα monoclonal blocking antibodies (infliximab, adalimumab, certolizumab pegol, and golimumab), a soluble TNF receptor fusion protein (etanercept), an IL-6 receptor monoclonal blocking antibody (tocilizumab), and IL-1β-blocking therapies (anakinra and canakinumab). These treatments are generally very effective in the reduction of inflammation and associated bone/cartilage destruction. Of interest, it is known that many of these cytokines are also important contributors to angiogenesis and may even work in part by reducing neovascularization in the arthritic joint. TNFα alone can promote angiogenesis and is also able to regulate neovascularization through interactions with the Ang/Tie-2 pathway . In addition, IL-17 synergizes with TNFα to stimulate the production of VEGF and other growth factors by FLS. It was also determined that IL-1β is able to promote VEGF production by FLS . Shu et al. established that blocking TNFα in EC using certolizumab pegol inhibited leukocyte adhesion through downregulation of adhesion molecules (E-selectin, ICAM-1, and VCAM-1), as well as a significant decrease in pro-angiogenic chemokine production, all of which led to a significant decrease in angiogenesis . Furthermore, immature blood vessels in the RA synovium are selectively depleted in response to anti-TNF therapy . Inhibiting IL-6 receptor signaling also leads to a clear decrease in VEGF levels in RA . These studies further support the notion that part of the mechanism of action for these types of effective antirheumatic therapies may be through the inhibition of angiogenesis.
As IL-17 contributes not only to synovial angiogenesis but also to other pathological processes in RA, inhibition of this pathway is currently under investigation as a treatment modality in RA and other inflammatory joint diseases. Several preclinical models of arthritis established that the neutralization of IL-17 reduces disease severity and joint destruction . Interestingly, anti-CXCL5 therapy ameliorates IL-17-induced arthritis by decreasing joint vascularization . Phase II clinical trials with two different IL-17-targeting monoclonal antibodies, secukinumab and ixekizumab, showed encouraging results in RA patients . Given the pro-angiogenic role of IL-17, a reduction in synovial neovascularization may contribute to the efficacy of these therapies; however, this still remains to be demonstrated.
Chemokines
Targeting pro-angiogenic chemokines or their receptors may be an effective approach to ameliorate RA. A possible target in this respect is the CXCL12–CXCR4/CXCR7 signaling axis. CXCL12 is an important chemotactic molecule that attracts EPCs to the site of blood vessel formation and can also act as an attractant for inflammatory cells . CXCR4 and CXCR7 are the corresponding receptors for CXCL12, and all three molecules have been demonstrated to be increased in RA synovial tissues and fluid . Recently, a humanized antibody targeting CXCL12 was described, which significantly ameliorated arthritis in the CIA model, and combination therapy with a TNF antagonist was additive . AMD3100, a potent antagonist of CXCR4, was shown to inhibit arthritis in the CIA mouse model through a clear reduction in immune cell infiltration as well as joint destruction. Interestingly, serum levels of IL-6 were also significantly reduced upon treatment with this compound . Another compound inhibiting CXCR4 signaling, a T140 analog, also exhibited similar effects Likewise, the CXCR7 antagonist CCX733 also led to a reduction in clinical arthritis scores in the CIA mouse model in association with a significant reduction in the number of blood vessels in the inflamed synovial tissues . Several pharmacological inhibitors of this axis are currently in phase II clinical trials for multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, Hodgkin disease, and myocardial infarction . AMD3100, also known as Plerixafor, is already approved by the Food and Drug Administration (FDA) and is currently being used in the treatment of multiple myeloma and non-Hodgkin’s lymphoma . Although these compounds have not yet been tested in clinical trials for RA, it is possible that they may also have a beneficial effect on inflammatory arthritis.
Intracellular signaling pathways
Mounting evidence shows that the Ang/Tie-2 system is an important mediator of synovial angiogenesis . Targeting this system using a Tie-2 antibody significantly decreased arthritis severity as well as neovascularization in the CIA model . This is in congruence with work done by Chen et al. in which gene therapy was used to administer a soluble Tie-2 receptor before and after the onset of arthritis, also in the CIA model. Overexpression of the soluble receptor before arthritis induction significantly inhibited onset, incidence, and severity, whereas administration after onset also significantly decreased disease severity as well as the number of synovial blood vessels . Currently, there are no clinical trials testing the efficacy of inhibition of this pathway in rheumatoid arthritis; however, clinical trials investigating such inhibitors in oncology are ongoing. AMG-386 (trebananib), an Fc fusion protein that works through the inhibition of Ang-1 and Ang-2 binding to the Tie-2 receptor, is currently in several clinical trials in the treatment of renal cell carcinoma, and ovarian, gastrointestinal, breast, and prostate cancer among others. Monoclonal antibodies directed against Tie-2 and Tie-2 TKIs are also being studied for their efficacy in the treatment of various cancers .
NF-κB signaling is also an attractive target in the treatment of RA, as it is a central regulator of numerous pro-inflammatory and pro-angiogenic molecules, including TNFα, IL-1β, IL-6, IL-8, GM-CSF, CCL2, CCL3, CCL5, ICAM-1, and VCAM-1 . Various strategies to target the canonical NF-κB pathway, including decoy oligonucleotides , gene therapeutic approaches , and selective small molecule inhibitors or peptides , have all been proven very effective in reducing arthritis severity and joint destruction. In a number of studies, this was accompanied by a decrease in serum levels of pro-angiogenic factors, as well as by an increase in the levels of angiostatic molecules . However, a detailed analysis of the effects on synovial vascularization after targeting this pathway is, thus far, lacking. To study this in more detail, NF-κB inhibitors could be targeted specifically to ECs using a multimodular recombinant protein that specifically binds to the cytokine-activated endothelium, which works very elegantly under inflammatory conditions in vivo and results in amelioration of the disease course in murine models of RA . However, also in this study, the effects of this intervention on angiogenesis were not reported (yet). Another recent study described the identification of several peptides that selectively bound to the vasculature of inflamed joints and inhibited angiogenesis. Intravenous injection of these peptides in a rat model of arthritis resulted in a dose-dependent reduction of arthritis severity, which could be attributed in part to a reduction of immune cell trafficking into the joint and inhibition of angiogenesis . Interestingly, these peptides could also be used to selectively deliver inhibitors of the canonical NF-κB pathway to the vasculature of inflamed joints.
Initial studies also demonstrate a role for the noncanonical NF-κB pathway, with its main regulator NF-κB-inducing kinase (NIK), in synovial angiogenesis in RA. Mice deficient in NIK expression were observed to have significantly less inflammation in the AIA model as well as a reduction in synovial blood vessels . Taken together, these data suggest that targeting of the NF-κB pathway in arthritis results in substantial therapeutic benefit, which may be, in part, due to inhibition of angiogenesis.
Histone deacetylase inhibitors (HDACi) are currently in clinical trials for rheumatic diseases and, recently, beneficial effects have been described in systemic juvenile inflammatory arthritis. Oral administration of the nonselective HDACi givinostat (ITF2357) resulted in significant therapeutic benefit after 12 weeks, particularly with respect to arthritis activity, with a relatively good safety profile . Interestingly, preclinical studies demonstrated that HDACi not only suppress inflammation but also inhibits VEGF, CCL2, CCL5, and CXCL12 production by intact RA synovial biopsies ex vivo .
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