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1.  Cortical remodeling during menopause, rheumatoid arthritis, glucocorticoid and bisphosphonate therapy 
Bone mass, bone geometry and its changes are based on trabecular and cortical bone remodeling. Whereas the effects of estrogen loss, rheumatoid arthritis (RA), glucocorticoid (GC) and bisphosphonate (BP) on trabecular bone remodeling have been well described, the effects of these conditions on the cortical bone geometry are less known. The present review will report current knowledge on the effects of RA, GC and BP on cortical bone geometry and its clinical relevance. Estrogen deficiency, RA and systemic GC lead to enhanced endosteal bone resorption. While in estrogen deficiency and under GC therapy endosteal resorption is insufficiently compensated by periosteal apposition, RA is associated with some periosteal bone apposition resulting in a maintained load-bearing capacity and stiffness. In contrast, BP treatment leads to filling of endosteal bone cavities at the epiphysis; however, periosteal apposition at the bone shaft seems to be suppressed. In summary, estrogen loss, RA and GC show similar effects on endosteal bone remodeling with an increase in bone resorption, whereas their effect on periosteal bone remodeling may differ. Despite over 50 years of GC therapy and over 25 years of PB therapy, there is still need for better understanding of the skeletal effects of these drugs as well as of inflammatory disease such as RA on cortical bone remodeling.
doi:10.1186/ar4180
PMCID: PMC3672822  PMID: 23521873
2.  T cells as key players for bone destruction in gouty arthritis? 
The deposition of monosodium urate (MSU) crystals in synovial fluid and tissue leads to gouty arthritis frequently associated with synovial inflammation and bone erosions. The cellular mechanism that links MSU crystals to an increased number of osteoclasts has not yet been fully understood. In a recent issue of Arthritis Research & Therapy Lee and colleagues proposed that bone destruction in chronic gouty arthritis is at least in part dependent on expression by T cells of receptor activator of NF-κB ligand (RANKL). The authors showed that pro-resorptive cytokines such as IL-1β, IL-6, and TNFα are expressed within tophi and stromal infiltrates. In vitro stimulation with MSU crystals revealed monocytes as a source for these cytokines, whereas T cells produce RANKL, the major trigger of osteoclastogenesis.
doi:10.1186/ar3508
PMCID: PMC3334629  PMID: 22136246
4.  Biochemical markers of ongoing joint damage in rheumatoid arthritis - current and future applications, limitations and opportunities 
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond.
doi:10.1186/ar3280
PMCID: PMC3132026  PMID: 21539724
6.  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
7.  RANKL inhibition by osteoprotegerin prevents bone loss without affecting local or systemic inflammation parameters in two rat arthritis models: comparison with anti-TNFα or anti-IL-1 therapies 
Arthritis Research & Therapy  2009;11(6):R187.
Introduction
Rat adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) feature bone loss and systemic increases in TNFα, IL-1β, and receptor activator of NF-κB ligand (RANKL). Anti-IL-1 or anti-TNFα therapies consistently reduce inflammation in these models, but systemic bone loss often persists. RANKL inhibition consistently prevents bone loss in both models without reducing joint inflammation. Effects of these therapies on systemic markers of bone turnover and inflammation have not been directly compared.
Methods
Lewis rats with established AIA or CIA were treated for 10 days (from day 4 post onset) with either PBS (Veh), TNFα inhibitor (pegsunercept), IL-1 inhibitor (anakinra), or RANKL inhibitor (osteoprotegerin (OPG)-Fc). Local inflammation was evaluated by monitoring hind paw swelling. Bone mineral density (BMD) of paws and lumbar vertebrae was assessed by dual X-ray absorptiometry. Markers and mediators of bone resorption (RANKL, tartrate-resistant acid phosphatase 5b (TRACP 5B)) and inflammation (prostaglandin E2 (PGE2), acute-phase protein alpha-1-acid glycoprotein (α1AGP), multiple cytokines) were measured in serum (day 14 post onset).
Results
Arthritis progression significantly increased paw swelling and ankle and vertebral BMD loss. Anti-TNFα reduced paw swelling in both models, and reduced ankle BMD loss in AIA rats. Anti-IL-1 decreased paw swelling in CIA rats, and reduced ankle BMD loss in both models. Anti-TNFα and anti-IL-1 failed to prevent vertebral BMD loss in either model. OPG-Fc reduced BMD loss in ankles and vertebrae in both models, but had no effect on paw swelling. Serum RANKL was elevated in AIA-Veh and CIA-Veh rats. While antiTNFα and anti-IL-1 partially normalized serum RANKL without any changes in serum TRACP 5B, OPG-Fc treatment reduced serum TRACP 5B by over 90% in both CIA and AIA rats. CIA-Veh and AIA-Veh rats had increased serum α1AGP, IL-1β, IL-8 and chemokine (C-C motif) ligand 2 (CCL2), and AIA-Veh rats also had significantly greater serum PGE2, TNFα and IL-17. Anti-TNFα reduced systemic α1AGP, CCL2 and PGE2 in AIA rats, while anti-IL-1 decreased systemic α1AGP, IL-8 and PGE2. In contrast, RANKL inhibition by OPG-Fc did not lessen systemic cytokine levels in either model.
Conclusions
Anti-TNFα or anti-IL-1 therapy inhibited parameters of local and systemic inflammation, and partially reduced local but not systemic bone loss in AIA and CIA rats. RANKL inhibition prevented local and systemic bone loss without significantly inhibiting local or systemic inflammatory parameters.
doi:10.1186/ar2879
PMCID: PMC3003514  PMID: 20003323
8.  Hypoxia. Hypoxia in the pathogenesis of systemic sclerosis 
Autoimmunity, microangiopathy and tissue fibrosis are hallmarks of systemic sclerosis (SSc). Vascular alterations and reduced capillary density decrease blood flow and impair tissue oxygenation in SSc. Oxygen supply is further reduced by accumulation of extracellular matrix (ECM), which increases diffusion distances from blood vessels to cells. Therefore, severe hypoxia is a characteristic feature of SSc and might contribute directly to the progression of the disease. Hypoxia stimulates the production of ECM proteins by SSc fibroblasts in a transforming growth factor-β-dependent manner. The induction of ECM proteins by hypoxia is mediated via hypoxia-inducible factor-1α-dependent and -independent pathways. Hypoxia may also aggravate vascular disease in SSc by perturbing vascular endothelial growth factor (VEGF) receptor signalling. Hypoxia is a potent inducer of VEGF and may cause chronic VEGF over-expression in SSc. Uncontrolled over-expression of VEGF has been shown to have deleterious effects on angiogenesis because it leads to the formation of chaotic vessels with decreased blood flow. Altogether, hypoxia might play a central role in pathogenesis of SSc by augmenting vascular disease and tissue fibrosis.
doi:10.1186/ar2598
PMCID: PMC2688169  PMID: 19473554
9.  Osteoimmunology in rheumatic diseases 
This review summarizes the recent advances of osteoimmunology, a new research field that investigates the interaction of the immune system with the skeleton. Osteoimmunology has contributed significantly to the understanding of joint destruction in rheumatoid arthritis and other forms of arthropathies. In particular, the molecular regulation of osteoclast formation and its control by proinflammatory cytokines have helped investigators to understand the mechanisms of bone erosion in rheumatic diseases. Osteoimmunology has also allowed an improvement in our knowledge of the structure-sparing effects of antirheumatic drug therapy. Moreover, recent advances in the understanding of the molecular regulation of osteophyte formation are based on the characterization of the regulation of bone formation by inflammation. This review highlights the key insights into the regulation of bone destruction and formation in arthritis. Moreover, concepts of how bone influences the immune system are discussed.
doi:10.1186/ar2571
PMCID: PMC2688223  PMID: 19232069
10.  Erosive arthritis 
Arthritis Research & Therapy  2007;9(Suppl 1):S2.
Inflammation and degradation of bone are two closely linked processes. Chronic inflammatory arthritis not only leads to inflammatory bone loss but it also involves local erosion of articular bone. This osteo-destructive feature of chronic inflammatory arthritis is a major cause of disability in patients with rheumatoid arthritis. Osteoclasts are essential for the resorption of mineralized cartilage and subchondral bone in chronic arthritis. The observed up-regulation of osteoclast differentiation factors (receptor activator of nuclear factor-κB ligand [RANKL]) in the synovial membrane of chronically inflamed joints indicates that osteoclasts are abundant in this setting, leading to rapid degradation of mineralized tissue. Blockade of osteoclast formation is thus a key strategy in preventing structural damage in arthritis. Denosumab, a humanized antibody that neutralizes RANKL, is an attractive candidate agent to inhibit inflammatory bone loss.
doi:10.1186/ar2166
PMCID: PMC1924517  PMID: 17634141
11.  Cells of the synovium in rheumatoid arthritis. Osteoclasts 
Osteoclasts are multinucleated cells of hematopoietic origin and are the primary bone resorbing cells. Numerous osteoclasts are found within the synovial tissue at sites adjacent to bone, creating resorption pits and local bone destruction. They are equipped with specific enzymes and a proton pump that enable them to degrade bone matrix and solubilize calcium, respectively. The synovial tissue of inflamed joints has a particularly high potential to accumulate osteoclasts because it harbors monocytes/macrophages, which function as osteoclast precursors, as well as cells that provide the specific molecular signals that drive osteoclast formation. Osteoclasts thus represent a link between joint inflammation and structural damage since they resorb mineralized tissue adjacent to the joint and destroy the joint architecture.
doi:10.1186/ar2110
PMCID: PMC1860063  PMID: 17316459
12.  Imbalance of local bone metabolism in inflammatory arthritis and its reversal upon tumor necrosis factor blockade: direct analysis of bone turnover in murine arthritis 
Chronic arthritis typically leads to loss of periarticular bone, which results from an imbalance between bone formation and bone resorption. Recent research has focused on the role of osteoclastogenesis and bone resorption in arthritis. Bone resorption cannot be observed isolated, however, since it is closely linked to bone formation and altered bone formation may also affect inflammatory bone loss. To simultaneously assess bone resorption and bone formation in inflammatory arthritis, we developed a histological technique that allows visualization of osteoblast function by in-situ hybridization for osteocalcin and osteoclast function by histochemistry for tartrate-resistant acid phosphatase. Paw sections from human tumor necrosis factor transgenic mice, which develop an erosive arthritis, were analyzed at three different skeletal sites: subchondral bone erosions, adjacent cortical bone channels, and endosteal regions distant from bone erosions. In subchondral bone erosions, osteoclasts were far more common than osteoblasts. In contrast, cortical bone channels underneath subchondral bone erosions showed an accumulation of osteoclasts but also of functional osteoblasts resembling a status of high bone turnover. In contrast, more distant skeletal sites showed only very low bone turnover with few scattered osteoclasts and osteoblasts. Within subchondral bone erosions, osteoclasts populated the subchondral as well as the inner wall, whereas osteoblasts were almost exclusively found along the cortical surface. Blockade of tumor necrosis factor reversed the negative balance of bone turnover, leading to a reduction of osteoclast numbers and enhanced osteoblast numbers, whereas the blockade of osteoclastogenesis by osteoprotegerin also abrogated the osteoblastic response. These data indicate that bone resorption dominates at skeletal sites close to synovial inflammatory tissue, whereas bone formation is induced at more distant sites attempting to counter-regulate bone resorption.
doi:10.1186/ar1872
PMCID: PMC1526585  PMID: 16507121
13.  Tumour necrosis factor activates the mitogen-activated protein kinases p38α and ERK in the synovial membrane in vivo 
Arthritis Research & Therapy  2005;7(5):R1140-R1147.
Tumour necrosis factor (TNF) is considered to be a major factor in chronic synovial inflammation and is an inducer of mitogen-activated protein kinase (MAPK) signalling. In the present study we investigated the ability of TNF to activate MAPKs in the synovial membrane in vivo. We studied human TNF transgenic mice – an in vivo model of TNF-induced arthritis – to examine phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK) and p38MAPKα in the inflamed joints by means of immunoblot and immunohistochemistry. In addition, the effects of systemic blockade of TNF, IL-1 and receptor activator of nuclear factor-κB (RANK) ligand on the activation of MAPKs were assessed. In vivo, overexpression of TNF induced activation of p38MAPKα and ERK in the synovial membrane, whereas activation of JNK was less pronounced and rarely observed on immunohistochemical analysis. Activated p38MAPKα was predominantly found in synovial macrophages, whereas ERK activation was present in both synovial macrophages and fibroblasts. T and B lymphocytes did not exhibit major activation of any of the three MAPKs. Systemic blockade of TNF reduced activation of p38MAPKα and ERK, whereas inhibition of IL-1 only affected p38MAPKα and blockade of RANK ligand did not result in any decrease in MAPK activation in the synovial membrane. These data indicate that TNF preferentially activates p38MAPKα and ERK in synovial membrane exposed to TNF. This not only suggests that targeted inhibition of p38MAPKα and ERK is a feasible strategy for blocking TNF-mediated effects on joints, but it also shows that even currently available methods to block TNF effectively reduce activation of these two MAPKs.
doi:10.1186/ar1797
PMCID: PMC1257441  PMID: 16207331
14.  JNK1 is not essential for TNF-mediated joint disease 
Arthritis Research & Therapy  2004;7(1):R166-R173.
Tumour necrosis factor (TNF) signalling molecules are considered as promising therapeutic targets of antirheumatic therapy. Among them, mitogen-activated protein kinases are thought to be of central importance. Herein, we investigate the role in vivo of TNF-α signalling through c-Jun N-terminal kinase (JNK)1 in destructive arthritis. Human TNF transgenic (hTNFtg) mice, which develop inflammatory arthritis, were intercrossed with JNK1-deficient (JNK1-/-) mice. Animals (n = 35) of all four genotypes (wild-type, JNK1-/-, hTNFtg, JNK1-/-hTNFtg) were assessed for clinical and histological signs of arthritis. Clinical features of arthritis (swelling and decreased grip strength) developed equally in hTNFtg and JNK1-/-hTNFtg mice. Histological analyses revealed no differences in the quantity of synovial inflammation and bone erosions or in the cellular composition of the synovial infiltrate. Bone destruction and osteoclast formation were observed to a similar degree in hTNFtg and JNK1-/-hTNFtg animals. Moreover, cartilage damage, as indicated by proteoglycan loss in the articular cartilage, was comparable in the two strains. Intact phosphorylation of JNK and c-Jun as well as expression of JNK2 in the synovial tissue of JNK1-/-hTNFtg mice suggests that signalling through JNK2 may compensate for the deficiency in JNK1. Thus, JNK1 activation does not seem to be essential for TNF-mediated arthritis.
doi:10.1186/ar1473
PMCID: PMC1064897  PMID: 15642137
arthritis; JNK1; TNF-α transgenic
15.  The role of osteoprotegerin in arthritis 
Arthritis Research & Therapy  2003;5(5):239-245.
Bone erosion is a hallmark of rheumatoid arthritis. Recent evidence from experimental arthritis suggests that osteoclasts are essential for the formation of local bone erosions. Two essential regulators of osteoclastogenesis have recently been described: the receptor-activator of nuclear factor kappa B ligand, which promotes osteoclast maturation, and osteoprotegerin (OPG), which blocks osteoclastogenesis. The present review summarizes the current knowledge on the role of osteoclasts in local bone erosion. In addition, the role of OPG as a therapeutic tool to inhibit local bone erosion is addressed. Finally, evidence for OPG as an inhibitor of systemic inflammatory bone loss is discussed.
PMCID: PMC193736  PMID: 12932284
bone erosion; osteoclasts; osteoporosis; osteoprotegerin; rheumatoid arthritis

Results 1-15 (15)