A common feature of autoimmune diseases is the perpetual production of macrophage, dendritic and/or osteoclast effector cells, which mediate parenchymal tissue destruction in end organs. In support of this, we have demonstrated previously that patients and mice with inflammatory-erosive arthritis have a marked increase in circulating CD11b+ precursor cells, which are primed for osteoclastogenesis, and that this increase in osteoclast precursors (OCPs) is due to systemically increased TNF production. From these data, we proposed a unifying hypothesis to explain these osteoimmunologic findings during the pathogenesis of inflammatory-erosive arthritis, which has three postulates: (1) myelopoiesis chronically induced by TNF has profound effects on the bone marrow and joint tissues that should be evident from a longitudinal MRI; (2) TNF alters the chemokine/chemokine receptor axis in the bone marrow to stimulate OCP release into the blood, and (3) OCP-mediated lymphangiogenesis occurs in the end organ as a compensatory mechanism to drain the inflammation and remove by-products of joint catabolism. Here, we describe our recent experimental findings that support these hypotheses and speculate on how this information can be used as diagnostic biomarkers and tools to discover novel therapies to treat patients with inflammatory-erosive arthritis.
"One potential key variable in the development of arthritic flare is regional efferent lymphatic flow from RA joints. It has been known for almost 75 years that lymphatic vessels proliferate at sites of inflammation , but the contribution of lymph clearance has been largely overlooked until recently . Studies show that lymphatic clearance serves as a compensatory mechanism to mobilize and transport cells, interstitial fluid and catabolic factors produced during a chronic inflammatory response [12,13]. "
[Show abstract][Hide abstract] ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints. However, how arthritic flare occurs only in select joints during a systemic autoimmune disease remains an enigma. To better understand these observations, we developed longitudinal imaging outcomes of synovitis and lymphatic flow in mouse models of RA, and identified that asymmetric knee flare is associated with ipsilateral popliteal lymph node (PLN) collapse and the translocation of CD23(+)/CD21(hi) B-cells (B-in) into the paracortical sinus space of the node. In order to understand the relationship between this B-in translocation and lymph drainage from flaring joints, we tested the hypothesis that asymmetric tumor necrosis factor (TNF)-induced knee arthritis is associated with ipsilateral PLN and iliac lymph node (ILN) collapse, B-in translocation, and decreased afferent lymphatic flow.
TNF transgenic (Tg) mice with asymmetric knee arthritis were identified by contrast-enhanced (CE) magnetic resonance imaging (MRI), and PLN were phenotyped as "expanding" or "collapsed" using LNcap threshold = 30 (Arbitrary Unit (AU)). Inflammatory-erosive arthritis was confirmed by histology. Afferent lymphatic flow to PLN and ILN was quantified by near infrared imaging of injected indocyanine green (NIR-ICG). The B-in population in PLN and ILN was assessed by immunohistochemistry (IHC) and flow cytometry. Linear regression analyses of ipsilateral knee synovial volume and afferent lymphatic flow to PLN and ILN were performed.
Afferent lymph flow to collapsed nodes was significantly lower (P < 0.05) than flow to expanding nodes by NIR-ICG imaging, and this occurred ipsilaterally. While both collapsed and expanding PLN and ILN had a significant increase (P < 0.05) of B-in compared to wild type (WT) and pre-arthritic TNF-Tg nodes, B-in of expanding lymph nodes (LN) resided in follicular areas while B-in of collapsed LN were present within LYVE-1+ lymphatic vessels. A significant correlation (P < 0.002) was noted in afferent lymphatic flow between ipsilateral PLN and ILN during knee synovitis.
Asymmetric knee arthritis in TNF-Tg mice occurs simultaneously with ipsilateral PLN and ILN collapse. This is likely due to translocation of the expanded B-in population to the lumen of the lymphatic vessels, resulting in a dramatic decrease in afferent lymphatic flow. PLN collapse phenotype can serve as a new biomarker of knee flare.
[Show abstract][Hide abstract] ABSTRACT: Rheumatoid arthritis is characterized by systemic inflammation of synovial joints leading to erosion and cartilage destruction. Although efficacious anti-tumor necrosis factor α (TNF-α) biologic therapies exist, there is an unmet medical need for safe and more efficient treatment regimens for disease remission. We evaluated the anti-inflammatory effects of poly(dl-lactide-co-glycolide acid) (PLGA) nanoparticles loaded with small interfering RNA (siRNA) directed against TNF-α in vitro and in vivo. The siRNA-loaded PLGA nanoparticles mediated a dose-dependent TNF-α silencing in lipopolysaccharide-activated RAW 264.7 cells in vitro. The severity of collagen antibody-induced arthritis in DBA/1J mice was assessed by paw scoring and compared to the degree of magnetic resonance imaging (MRI)-quantified joint effusion and bone marrow edema. Two intra-articular treatments per joint with nanoparticles loaded with TNF-α siRNA (1 μg) resulted in a reduction in disease activity, evident by a significant decrease of the paw scores and joint effusions, as compared to treatment with PLGA nanoparticles loaded with non-specific control siRNA, whereas the degree of bone marrow edema in the tibial and femoral head remained unchanged. When the siRNA dose was 5 or 10 μg, there was no difference between the specific and the non-specific siRNA treatment groups. These findings suggest that MRI is a promising method for evaluation of early disease progression and treatment in murine arthritis models. In addition, proper siRNA dosing seems to be important for a positive therapeutic outcome in vivo. However, further studies are needed to fully clarify the mechanism(s) underlying the observed anti-inflammatory effects of the siRNA-loaded nanoparticles.
[Show abstract][Hide abstract] ABSTRACT: To compare the osteoclastogenic capacity of peripheral blood mononuclear cells (PBMCs) from patients with osteoarthritis (OA) to that of PBMCs from self-reported normal individuals.
PBMCs from 140 patients with OA and 45 healthy donors were assayed for CD14+ expression and induced to differentiate into osteoclasts over 3 weeks in vitro. We assessed the number of osteoclasts, their resorptive activity, osteoclast apoptosis, and expression of the following cytokine receptors: RANK, interleukin-1 receptor type I (IL-1RI), and IL-1RII. A ridge logistic regression classifier was developed to discriminate OA patients from controls.
PBMCs from OA patients gave rise to more osteoclasts that resorbed more bone surface than did PBMCs from controls. The number of CD14+ precursors was comparable in both groups, but there was less apoptosis in osteoclasts obtained from OA patients. Although no correlation was found between osteoclastogenic capacity and clinical or radiographic scores, levels of IL-1RI were significantly lower in cultures from patients with OA than in cultures from controls. Osteoclast apoptosis and expression levels of IL-1RI and IL-1RII were used to build a multivariate predictive model for OA.
During 3 weeks of culture under identical conditions, monocytes from patients with OA display enhanced capacity to generate osteoclasts compared to cells from controls. Enhanced osteoclastogenesis is accompanied by increased resorptive activity, reduced osteoclast apoptosis, and diminished IL-1RI expression. These findings support the possibility that generalized changes in bone metabolism affecting osteoclasts participate in the pathophysiology of OA.
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