Bone morphogenetic proteins in destructive and remodeling arthritis

Joint destruction and tissue responses determine the outcome of chronic arthritis. Joint inflammation and damage are often the dominant clinical presentation. However, in some arthritic diseases, in particular the spondyloarthritides, joint remodeling is a prominent feature, with new cartilage and bone formation leading to ankylosis and contributing to loss of function. A role for bone morphogenetic proteins in joint remodeling has been demonstrated in the formation of both enthesophytes and osteophytes. Data from genetic models support a role for bone morphogenetic protein signaling in cartilage homeostasis. Finally, this signaling pathway is likely to play a steering role in the synovium.     

基质金属蛋白酶与类风湿性关节炎

类风湿性关节炎是一种慢性炎症性自身免疫性疾病,其特点是软骨和骨骼的不可逆损伤。基质金属蛋白酶参与结缔组织重塑,在关节环境炎症级联中起着重要作用,或可成为类风湿性关节炎治疗的潜在新靶点。本文就其在类风湿性关节炎发生发展和治疗中的研究进展作一综述。     

Dynamic activation of bone morphogenetic protein signaling in collagen-induced arthritis supports their role in joint homeostasis and disease

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.     

Migratory potential of rheumatoid arthritis synovial fibroblasts: Additional perspectives

Cell migration is a central part of physiological and pathophysiological processes including wound healing, immune defense, matrix remodeling and organ homeostasis. Different cell types have migratory potential including cells of the immune system and cells required in wound healing and tissue repair. These cells migrate locally through the tissue to the site of damage. The fibroblast is a central cell type of wound healing. In rheumatoid arthritis (RA), activated synovial fibroblasts (SFs) have the ability to invade joint cartilage, actively contributing to joint destruction in RA. Recently, RASFs have been shown to be able to migrate to non-affected areas and joints through the blood stream and to invade distant cartilage. RASFs most likely use similar mechanisms comparable to lymphocytes and tumor cells for long-distance and vascular trans-migration. Future experiments will address the goal to keep the transformed-appearing fibroblasts in the affected joints using therapeutical strategies that inhibit the pathophysiological changes of transformed-appearing RASFs but do not interfere with the physiological processes of ‘normal’ fibroblasts.     

Angiogenesis in the pathogenesis of inflammatory joint and lung diseases

This paper reviews hypotheses about roles of angiogenesis in the pathogenesis of inflammatory disease in two organs, the synovial joint and the lung. Neovascularisation is a fundamental process for growth and tissue repair after injury. Nevertheless, it may contribute to a variety of chronic inflammatory diseases, including rheumatoid arthritis, osteoarthritis, asthma, and pulmonary fibrosis. Inflammation can promote angiogenesis, and new vessels may enhance tissue inflammation. Angiogenesis in inflammatory disease may also contribute to tissue growth, disordered tissue perfusion, abnormal ossification, and enhanced responses to normal or pathological stimuli. Angiogenesis inhibitors may reduce inflammation and may also help to restore appropriate tissue structure and function.     

Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patients with osteoarthritis and rheumatoid arthritis

Bone morphogenetic proteins (BMPs) have been identified as important morphogens with pleiotropic functions in regulating the development, homeostasis and repair of various tissues. The aim of this study was to characterize the expression of BMPs in synovial tissues under normal and arthritic conditions. Synovial tissue from normal donors (ND) and from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were analyzed for BMP expression by using microarray hybridization. Differential expression of BMP-4 and BMP-5 was validated by semiquantitative RT-PCR, in situ hybridization and immunohistochemistry. Activity of arthritis was determined by routine parameters for systemic inflammation, by histological scoring of synovitis and by semiquantitative RT-PCR of IL-1β, TNF-α, stromelysin and collagenase I in synovial tissue. Expression of BMP-4 and BMP-5 mRNA was found to be significantly decreased in synovial tissue of patients with RA in comparison with ND by microarray analysis (p < 0.0083 and p < 0.0091). Validation by PCR confirmed these data in RA (p < 0.002) and also revealed a significant decrease in BMP-4 and BMP-5 expression in OA compared with ND (p < 0.015). Furthermore, histomorphological distribution of both morphogens as determined by in situ hybridization and immunohistochemistry showed a dominance in the lining layer of normal tissues, whereas chronically inflamed tissue from patients with RA revealed BMP expression mainly scattered across deeper layers. In OA, these changes were less pronounced with variable distribution of BMPs in the lining and sublining layer. BMP-4 and BMP-5 are expressed in normal synovial tissue and were found decreased in OA and RA. This may suggest a role of distinct BMPs in joint homeostasis that is disturbed in inflammatory and degenerative joint diseases. In comparison with previous reports, these data underline the complex impact of these factors on homeostasis and remodeling in joint physiology and pathology.     

Saposin C coupled lipid nanovesicles specifically target arthritic mouse joints for optical imaging of disease severity

Rheumatoid arthritis is a chronic inflammatory disease affecting approximately 1% of the population and is characterized by cartilage and bone destruction ultimately leading to loss of joint function. Early detection and intervention of disease provides the best hope for successful treatment and preservation of joint mobility and function. Reliable and non-invasive techniques that accurately measure arthritic disease onset and progression are lacking. We recently developed a novel agent, SapC-DOPS, which is composed of the membrane-associated lysosomal protein saposin C (SapC) incorporated into 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) lipid nanovesicles. SapC-DOPS has a high fusogenic affinity for phosphatidylserine-enriched microdomains on surfaces of target cell membranes. Incorporation of a far-red fluorophore, CellVue Maroon (CVM), into the nanovesicles allows for in vivo non-invasive visualization of the agent in targeted tissue. Given that phosphatidylserine is present only on the inner leaflet of healthy plasma membranes but is "flipped" to the outer leaflet upon cell damage, we hypothesized that SapC-DOPS would target tissue damage associated with inflammatory arthritis due to local surface-exposure of phosphatidylserine. Optical imaging with SapC-DOPS-CVM in two distinct models of arthritis, serum-transfer arthritis (e.g., K/BxN) and collagen-induced arthritis (CIA) revealed robust SapC-DOPS-CVM specific localization to arthritic paws and joints in live animals. Importantly, intensity of localized fluorescent signal correlated with macroscopic arthritic disease severity and increased with disease progression. Flow cytometry of cells extracted from arthritic joints demonstrated that SapC-DOPS-CVM localized to an average of 7-8% of total joint cells and primarily to CD11b+Gr-1+ cells. Results from the current studies strongly support the application of SapC-DOPS-CVM for advanced clinical and research applications including: detecting early arthritis onset, assessing disease progression real-time in live subjects, and providing novel information regarding cell types that may mediate arthritis progression within joints.     

Current and future uses of skeletal stem cells for bone regeneration

The postnatal skeleton undergoes growth, modeling, and remodeling. The human skeleton is a composite of diverse tissue types, including bone, cartilage, fat, fibroblasts, nerves, blood vessels, and hematopoietic cells. Fracture nonunion and bone defects are among the most challenging clinical problems in orthopedic trauma. The incidence of nonunion or bone defects following fractures is increasing. Stem and progenitor cells mediate homeostasis and regeneration in postnatal tissue, including bone tissue. As multipotent stem cells, skeletal stem cells (SSCs) have a strong effect on the growth, differentiation, and repair of bone regeneration. In recent years, a number of important studies have characterized the hierarchy, differential potential, and bone formation of SSCs. Here, we describe studies on and applications of SSCs and/or mesenchymal stem cells for bone regeneration.     

Mesenchymal stem cells from development to postnatal joint homeostasis, aging, and disease

Joint morphogenesis involves signaling pathways and growth factors that recur in the adult life with less redundancy to safeguard joint homeostasis. Loss of such homeostasis due to abnormal signaling networks as in aging could lead to diseases such as osteoarthritis. Stem cells are the cellular counterpart and targets of the morphogenetic signals, and they function to maintain the tissues by ensuring replacement of cells lost to physiological turnover, injury, aging, and disease. Mesenchymal stem cells (MSCs) are key players in regenerative medicine for their ability to differentiate toward multiple lineages such as cartilage and bone, but they age along the host body and senesce when serially passaged in culture. Understanding correlations between aging and its effects on MSCs is of the utmost importance to explain how aging happens and unravel the underlying mechanisms. The investigation of the MSC senescence in culture will help in developing more efficient and standardized cell culture methods for cellular therapies in skeletal regenerative medicine. An important area to explore in biomedical sciences is the role of endogenous stem cell niches in joint homeostasis, remodeling, and disease. It is anticipated that an understanding of the stem cell niches and related remodeling signals will allow the development of pharmacological interventions to support effective joint tissue regeneration, to restore joint homeostasis, and to prevent osteoarthritis.     

Bone marrow mononuclear cells for joint therapy: The role of macrophages in inflammation resolution and tissue repair

Osteoarthritis (OA) is the most prevalent joint disease causing major disability and medical expenditures. Synovitis is a central feature of OA and is primarily driven by macrophages. Synovial macrophages not only drive inflammation but also its resolution, through a coordinated, simultaneous expression of pro- and anti-inflammatory mechanisms that are essential to counteract damage and recover homeostasis. Current OA therapies are largely based on anti-inflammatory principles and therefore block pro-inflammatory mechanisms such as prostaglandin E₂ and Nuclear factor-kappa B signaling pathways. However, such mechanisms are also innately required for mounting a pro-resolving response, and their blockage often results in chronic low-grade inflammation. Following minor injury, macrophages shield the damaged area and drive tissue repair. If the damage is more extensive, macrophages incite inflammation recruiting more macrophages from the bone marrow to maximize tissue repair and ultimately resolve inflammation. However, sustained damage and inflammation often overwhelms pro-resolving mechanisms of synovial macrophages leading to the chronic inflammation and related tissue degeneration observed in OA. Recently, experimental and clinical studies have shown that joint injection with autologous bone marrow mononuclear cells replenishes inflamed joints with macrophage and hematopoietic progenitors, enhancing mechanisms of inflammation resolution, providing remarkable and long-lasting effects. Besides creating an ideal environment for resolution with high concentrations of interleukin-10 and anabolic growth factors, macrophage progenitors also have a direct role in tissue repair. Macrophages constitute a large part of the early granulation tissue, and further transdifferentiate from myeloid into a mesenchymal phenotype. These cells, characterized as fibrocytes, are essential for repairing osteochondral defects. Ongoing “omics” studies focused on identifying key drivers of macrophage-mediated resolution of joint inflammation and those required for efficient osteochondral repair, have the potential to uncover ways for developing engineered macrophages or off-the-shelf pro-resolving therapies that can benefit patients suffering from many types of arthropaties, not only OA.     

Engineering custom-designed osteochondral tissue grafts

Tissue engineering is expected to help us outlive the failure of our organs by enabling the creation of tissue substitutes capable of fully restoring the original tissue function. Degenerative joint disease, which affects one-fifth of the US population and is the country's leading cause of disability, drives current research of actively growing, functional tissue grafts for joint repair. Toward this goal, living cells are used in conjunction with biomaterial scaffolds (serving as instructive templates for tissue development) and bioreactors (providing environmental control and molecular and physical regulatory signals). In this review, we discuss the requirements for engineering customized, anatomically-shaped, stratified grafts for joint repair and the challenges of designing these grafts to provide immediate functionality (load bearing, structural support) and long-term regeneration (maturation, integration, remodeling).     

Longstanding Hyperthyroidism Is Associated with Normal or Enhanced Intrinsic Cardiomyocyte Function despite Decline in Global Cardiac Function

Thyroid hormones (THs) play a pivotal role in cardiac homeostasis. TH imbalances alter cardiac performance and ultimately cause cardiac dysfunction. Although short-term hyperthyroidism typically leads to heightened left ventricular (LV) contractility and improved hemodynamic parameters, chronic hyperthyroidism is associated with deleterious cardiac consequences including increased risk of arrhythmia, impaired cardiac reserve and exercise capacity, myocardial remodeling, and occasionally heart failure. To evaluate the long-term consequences of chronic hyperthyroidism on LV remodeling and function, we examined LV isolated myocyte function, chamber function, and whole tissue remodeling in a hamster model. Three-month-old F1b hamsters were randomized to control or 10 months TH treatment (0.1% grade I desiccated TH). LV chamber remodeling and function was assessed by echocardiography at 1, 2, 4, 6, 8, and 10 months of treatment. After 10 months, terminal cardiac function was assessed by echocardiography and LV hemodynamics. Hyperthyroid hamsters exhibited significant cardiac hypertrophy and deleterious cardiac remodeling characterized by myocyte lengthening, chamber dilatation, decreased relative wall thickness, increased wall stress, and increased LV interstitial fibrotic deposition. Importantly, hyperthyroid hamsters demonstrated significant LV systolic and diastolic dysfunction. Despite the aforementioned remodeling and global cardiac decline, individual isolated cardiac myocytes from chronically hyperthyroid hamsters had enhanced function when compared with myocytes from untreated age-matched controls. Thus, it appears that long-term hyperthyroidism may impair global LV function, at least in part by increasing interstitial ventricular fibrosis, in spite of normal or enhanced intrinsic cardiomyocyte function.     

IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis.

T cell IL-17 displays proinflammatory properties and is expressed in the synovium of patients with rheumatoid arthritis. Its contribution to the arthritic process has not been identified. Here, we show that blocking of endogenous IL-17 in the autoimmune collagen-induced arthritis model results in suppression of arthritis. Also, joint damage was significantly reduced. In contrast, overexpression of IL-17 enhanced collagen arthritis. Moreover, adenoviral IL-17 injected in the knee joint of type II collagen-immunized mice accelerated the onset and aggravated the synovial inflammation at the site. Radiographic and histologic analysis showed markedly increased joint destruction. Elevated levels of IL-1beta protein were found in synovial tissue. Intriguingly, blocking of IL-1alphabeta with neutralizing Abs had no effect on the IL-17-induced inflammation and joint damage in the knee joint, implying an IL-1 independent pathway. This direct potency of IL-17 was underscored in the unabated IL-17-induced exaggeration of bacterial cell wall-induced arthritis in IL-1beta(-/-) mice. In conclusion, this data shows that IL-17 contributes to joint destruction and identifies an IL-1-independent role of IL-17. These findings suggest IL-17 to be a novel target for the treatment of destructive arthritis and may have implications for tissue destruction in other autoimmune diseases.     

A Metabolically-Stabilized Phosphonate Analog of Lysophosphatidic Acid Attenuates Collagen-Induced Arthritis

Rheumatoid arthritis (RA) is a destructive arthropathy with systemic manifestations, characterized by chronic synovial inflammation. Under the influence of the pro-inflammatory milieu synovial fibroblasts (SFs), the main effector cells in disease pathogenesis become activated and hyperplastic while releasing a number of signals that include pro-inflammatory factors and tissue remodeling enzymes. Activated RA SFs in mouse or human arthritic joints express significant quantities of autotaxin (ATX), a lysophospholipase D responsible for the majority of lysophosphatidic acid (LPA) production in the serum and inflamed sites. Conditional genetic ablation of ATX from SFs resulted in attenuation of disease symptoms in animal models, an effect attributed to diminished LPA signaling in the synovium, shown to activate SF effector functions. Here we show that administration of 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA), a metabolically stabilized analog of LPA and a dual function inhibitor of ATX and pan-antagonist of LPA receptors, attenuates collagen induced arthritis (CIA) development, thus validating the ATX/LPA axis as a novel therapeutic target in RA.     

How Does Joint Remodeling Work?: New Insights in the Molecular Regulation of the Architecture of Joints

Remodeling of joints is a key feature of inflammatory and degenerative joint disease. Bone erosion, cartilage degeneration and growth of bony spurs termed osteophytes are key features of structural joint pathology in the course of arthritis, which lead to impairment of joint function. Understanding their molecular mechanisms is essential to tailor targeted therapeutic approaches to protect joint architecture from inflammatory and mechanical stress. This addendum summarizes the new insights in the molecular regulation of bone formation in the joint and its relation to bone resorption. It describes how inflammatory cytokines impair bone formation and block the repair response of joints towards inflammatory stimuli. It particularly points out the key role of Dickkopf-1 protein, a regulator of the Wingless signaling and inhibitor of bone formation. This new link between inflammation and bone formation is also crucial for explaining the generation of osteophytes, bony spurs along joints, which are characterized by new bone and cartilage formation. This mechanism is largely dependent on an activation of wingless protein signaling and can lead to complete joint fusion. This addendum summarized the current concepts of joint remodeling in the limelight of these new findings.Key words: joint remodeling, arthritis, bone formation, bone erosion, osteoblasts, osteoclasts, Dickkopf, wingless proteinsJoints face profound remodeling in the course of arthritis. In humans, pathologic joint remodeling manifests as (i) destruction of joints due to bone erosion (rheumatoid arthritis), (ii) fusion of joints due to formation of bony spurs such as osteophytes, spondylophytes and syndesmophytes (ankylosing spondylitis) or (iii) a mixture of both changes (psoriatic arthritis). The molecular mechanisms determining these different forms of joint remodeling are not fully clarified, Insights in these mechanisms however are a clue to a deeper understanding of the architectural changes of human joints.Similar to systemic bone turnover, which most is most prominent in the trabecular bone compartment of the spine and long bones, joints are hot spots of bone remodeling during inflammatory disease. Cytokines expressed by inflammatory cells in the synovial membrane regulate local bone homeostasis and enable to remodel joints during disease—a process which can either lead to crippling and functional loss or to fusion and stabilization of the affected joint. Rheumatoid arthritis is characterized by bone erosions, which are the result of an enhanced bone resorption. In rheumatoid arthritis osteoclasts, the primary bone resorbing cells, accumulate and degrade the periarticular bone as well as the mineralized cartilage.¹ Molecularly increased osteoclast formation is based on the expression of macrophage colony-stimulating factor (MCSF) and receptor-antagonist of NFκB ligand (RANKL) in the synovial tissue, which both drive the differentiation of osteoclasts from monocytic precursors.^2–4 Osteoclasts are specialized cells to resorb bone and their local accumulation in the joint leads to a catabolic state, which by far outweighs bone formation resulting in a negative net effect of bone remodeling. Inflammatory cytokines, such as TNF, IL-1, IL-6 and IL-17 induce osteoclast formation by enhancing the expression of RANKL and promoting differentiation of osteoclast precursor cells to mature osteoclasts.^5–8 Abundance of proinflammatory cytokines in the synovial membrane of patients with RA, their induction of molecules involved in osteoclast formation and the influx of monocytes/macrophages serving as osteoclast precursor cells represent ideal prerequisites for osteoclast formation in joints.⁹The fact that appropriate repair strategies are virtually absent in patients with RA and that bone is hardly rebuilt when bone erosions have emerged, suggests activation of molecular signals, which blunt bone formation. Bone formation itself is regulated by growth factors and hormones, which stimulate differentiation and activity of osteoblasts. Typical regulators of bone formation constitute parathyroid hormone, prostaglandins, bone morphogenic proteins (BMPs) and wingless proteins (Wnt). Particularly the role of Wnt proteins in bone formation have achieved growing interest during the past few years, leading to identification of the LRP5/6 receptor as a key molecule for anabolic skeletal responses. Wnt proteins bind to the LRP5/6 receptor and lead to activation of a signal pathway involving GSK3 and β-catenin, which drive differentiation of mesenchymal cells into osteoblastogenesis.¹⁰ Regulators of Wnt- induced bone formation are Dickkopf (DKK) proteins, which competitively bind to LRP5/6 and prevent signaling activation by additionally engaging a negative coreceptor termed Kremen-1.^11,12 DKK proteins thus regulate bone homeostasis by interference with Wnt signaling.¹³We recently showed that inflammatory cytokines such as TNF induce DKK-1, a member of the DKK- family, which inhibits Wnt signaling. DKK-1 is highly expressed in inflammatory lesions of experimental arthritis and human rheumatoid arthritis.¹⁴ Moreover, increased levels can be detected in the serum of patients with RA, which depend on TNF. This is supported by the normalization of elevated DKK-1 levels in RA patients upon initiation of systemic TNF- blockade. Inhibition of DKK-1 in mice completely abolishes bone erosions in different models of experimental arthritis and leads to increased bone growth, which manifests as osteophyte formation in the joint.DKK-1 links the inflammation with bone formation as RANKL links inflammation with bone resorption. The fact that TNF and presumably also other inflammatory mediators induce both proteins explains the profound negative effect of inflammation on bone. Inflammation uncouples the balance between bone resorption and formation, enhancing the former by inducing RANKL and by repressing the latter by DKK-1. Also appears to be a tight cross talk between the Wnt- and RANKL-pathways.¹⁵ Inhibition of DKK-1 in arthritic mice lead to protection from bone erosions and osteoclasts did not appropriately form. This effect is based on the induction of osteoprotegerin (OPG) a natural decoy receptor for RANKL, which blocks RANKL and thus osteoclast formation. OPG is induced by Wnt proteins and shifts the balance from bone resorption to bone formation.In contrast to rheumatoid arthritis joints in ankylosing spondylitis and also in degenerative joint disease (osteoarthritis) show an attempt towards joint fusion rather than joint destruction. These bony spurs are the result of endochondral bone formation starting from the periosteum close to the joints, where osteoblasts differentiate build up bone matrix. We could demonstrate that Wnt proteins are crucially involved in this process since inhibition of DKK-1 lead to emergence of osteophytes and even complete fusion of joints. Taken together these data suggest that the balance of the Wnt/DKK system determines the remodeling of joints by governing bone destruction as well as osteophyte formation in joints (Fig. 1).Open in a separate windowFigure 1Patterns of joint remodeling.     

VEGF and bone cell signalling: an essential vessel for communication?

Vascular endothelial growth factor (VEGF) is an endothelial cell survival factor and is required for effective coupling of angiogenesis and osteogenesis. Although central to bone homeostasis, repair and the pathobiology that affect these processes, the precise mechanisms coupling endothelial cell function within bone formation and remodelling remain unclarified. This review will (i) focus on the potential directionality of VEGF signalling in adult bone by identifying the predominant source of VEGF within the bone microenvironment, (ii) will summarize current VEGF receptor expression studies by bone cells and (iii) will provide evidence for a role for VEGF signalling during postnatal repair and osteoporosis. A means of understanding the directionality of VEGF signalling in adult bone would allow us to most effectively target angiogenic pathways in diseases characterized by changes in bone remodelling rates and enhance bone repair when compromised. Copyright © 2012 John Wiley & Sons, Ltd.     

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.