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Key Points Bone homeostasis is dependent on the concerted actions of bone-building osteoblasts and bone-degrading osteoclasts — a process called bone remodelling. Two of the major factors that induce osteoblast differentiation and activation are: the signalling mediated by bone morphogenetic proteins via runt-related transcription factor 2; and the WNT–Frizzled–β-catenin pathway. Conversely, Dickkopf-related protein 1 (DKK1) and sclerostin inhibit osteoblast activation. Major molecules involved in osteoclast differentiation and activation include macrophage colony-stimulating factor and receptor activator of nuclear factor-κB (RANK) as well as its ligand (RANKL). Inflammation is associated with the overproduction of various cytokines, such as tumour necrosis factor, interleukin-1 (IL-1), IL-6 or IL-17. Their upregulation in the course of inflammation leads to excessive bone degradation mainly due to hyperactivation of osteoclasts, although some cytokines can also impair osteoblast function. Many diseases lead to inflammatory bone loss, including inflammatory bowel disease, chronic obstructive lung disease, cystic fibrosis, periodontitis, rheumatoid arthritis and other inflammatory diseases. Inflammatory bone loss is always systemic, and in some diseases — such as rheumatoid arthritis or periodontitis — it can also involve local bone. Therapies interfering with inflammation also affect systemic inflammatory bone loss, primarily by reducing the effects of cytokines on osteoclast activation; however, many of these treatments will not fully control inflammation. Owing to this ongoing inflammatory activity (even at low levels), bone loss will continue to accrue and therefore also requires specific targeting of bone cells. Bisphosphonates and denosumab are among the bone-targeting therapies that have been shown to be effective in treating inflammatory bone loss, but it is assumed that blockers of DKK1 and sclerostin — which are upregulated by cytokines and inhibit osteoblast repair mechanisms — are also likely to be effective. Bone continuously undergoes building and degradation — a process known as bone remodelling. This tightly controlled process can be dysregulated by chronic inflammation, and bone loss is commonly associated with inflammatory diseases. Here, Redlich and Smolen discuss the molecular mechanisms mediating the inflammatory loss of bone and present strategies and agents for therapeutic intervention. Bone is a tissue undergoing continuous building and degradation. This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes. Chronic inflammation can also perturb bone metabolism and promote increased bone loss. Inflammatory diseases can arise all over the body, including in the musculoskeletal system (for example, rheumatoid arthritis), the intestine (for example, inflammatory bowel disease), the oral cavity (for example, periodontitis) and the lung (for example, cystic fibrosis). Wherever inflammatory diseases occur, systemic effects on bone will ensue, as well as increased fracture risk. Here, we discuss the cellular and signalling pathways underlying, and strategies for therapeutically interfering with, the inflammatory loss of bone.

Myostatin is shown to directly promote osteoclast differentiation, and its inhibition improves arthritic bone loss in two mouse models. Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-β (TGF-β) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene ( Mstn ) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration 1 , 2 , 3 , 4 , 5 . However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone 6 , 7 , 8 , 9 , 10 , 11 . Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, a model for human RA 12 . Myostatin strongly accelerates receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast formation in vitro through transcription factor SMAD2-dependent regulation of nuclear factor of activated T-cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA.

Despite their different targets, biologic agents used for blockade of TNF and IL 6, inhibition of T cell co-stimulation and B cell depletion all have similar beneficial effects on the outcome of rheumatoid arthritis (RA). This observation raises questions as to whether the targets of these therapies might all be involved in a common pathogenetic pathway. In this Perspective, the authors discuss the disparities in RA therapy and whether clinical trial data can be used to determine at which point a biologic agent might interfere with the pathogenetic RA cascade. Despite their different targets, biologic agents used for blockade of TNF and IL-6, inhibition of T-cell co-stimulation and B-cell depletion all have similar beneficial effects on the outcome of rheumatoid arthritis (RA). This observation raises questions as to whether the targets of these therapies might all be involved in a common pathogenetic pathway. However, blockade of TNF and IL-6 has a similar inhibitory effect on joint damage progression in patients with either early or late disease. In comparison, B-cell depletion and inhibition of T-cell co-stimulation seem to have a somewhat delayed effect on joint damage (compared with cytokine inhibition), which suggests that these approaches affect upstream pathogenetic events. This article discusses these disparities and presents hypotheses as to whether clinical trial data can be used to determine at which point a biologic agent might interfere with the pathogenetic cascade in RA.

Blocking TNF effectively inhibits inflammation and structural damage in human rheumatoid arthritis (RA). However, so far it is unclear whether the effect of TNF is a direct one or indirect on up-regulation of other mediators. IL-1 may be one of these candidates because it has a central role in animal models of arthritis, and inhibition of IL-1 is used as a therapy of human RA. We removed the effects of IL-1 from a TNF-mediated inflammatory joint disease by crossing IL-1α and β-deficient mice (IL-1⁻/⁻) with arthritic human TNF-transgenic (hTNFtg) mice. Development of synovial inflammation was almost unaffected on IL-1 deficiency, but bone erosion and osteoclast formation were significantly reduced in IL-1⁻/⁻hTNFtg mice, compared with hTNFtg mice based on an intrinsic differentiation defect of IL-1-deficient monocytes. Most dramatically, however, cartilage damage was absent in IL-1⁻/⁻hTNFtg mice. Chimera studies revealed that protection of cartilage is based on the loss of IL-1 on hematopoietic, but not mesenchymal, cells, leading to decreased expression of ADAMTS-5 and MMP-3. These data show that TNF-mediated cartilage damage is completely and TNF-mediated bone damage is partially dependent on IL-1, suggesting that IL-1 is a crucial mediator for inflammatory cartilage and bone degradation.

Objective To elucidate the mechanisms involved in cartilage damage in an experimental model of rheumatoid arthritis (RA) by specifically addressing the time course of extracellular matrix degradation and the contribution of cell–matrix interactions for initiation and perpetuation of this process. Methods The human tumour necrosis factor (TNF) transgenic (hTNFtg) mouse model of RA was used to analyse the time course of pannus attachment to the cartilage and cartilage destruction, respectively, and crossed hTNFtg mice with interleukin (IL)-1−/− animals were used to investigate the role of IL-1 on these TNF-induced mechanisms in vivo. In addition, an in vitro attachment assay using synovial fibroblasts (SFs) from hTNFtg mice and freshly isolated articular cartilage was used to determine the role of proteoglycan loss in attachment of SFs and the role of the transmembrane heparan sulfate proteoglycan syndecan-4. Results In vivo analyses of hTNFtg mice showed that proteoglycan loss induced by IL-1 precedes and constitutes an important prerequisite for these processes as, in hTNFtg mice, IL-1 deficiency protected from the loss of cartilage proteoglycans and almost completely prevented the attachment and subsequent invasion of inflamed synovial tissue into cartilage. In vitro studies confirmed that loss of cartilage proteoglycans is required for attachment of SFs and that syndecan-4 is prominently involved in SF attachment and activation. Conclusions The results of this study suggest that the loss of cartilage proteoglycans is an early event in the course of destructive arthritis that facilitates the attachment of the inflamed synovial membrane and also initiates matrix degradation and inflammation through cell–matrix interactions.

Background Our aim was to investigate the role of nicotinic acetylcholine receptors (nAChRs) in in-vitro osteoclastogenesis and in in-vivo bone homeostasis. Methods The presence of nAChR subunits as well as the in-vitro effects of nAChR agonists were investigated by ex vivo osteoclastogenesis assays, real-time polymerase chain reaction, Western blot and flow cytometry in murine bone marrow-derived macrophages differentiated in the presence of recombinant receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The bone phenotype of mice lacking various nAChR subunits was investigated by peripheral quantitative computed tomography and histomorphometric analysis. Oscillations in the intracellular calcium concentration were detected by measuring the Fura-2 fluorescence intensity. Results We could demonstrate the presence of several nAChR subunits in bone marrow-derived macrophages stimulated with RANKL and M-CSF, and showed that they are capable of producing acetylcholine. nAChR ligands reduced the number of osteoclasts as well as the number of tartrate-resistant acidic phosphatase-positive mononuclear cells in a dose-dependent manner. In vitro RANKL-mediated osteoclastogenesis was reduced in mice lacking α7 homomeric nAChR or β2-containing heteromeric nAChRs, while bone histomorphometry revealed increased bone volume as well as impaired osteoclastogenesis in male mice lacking the α7 nAChR. nAChR ligands inhibited RANKL-induced calcium oscillation, a well-established phenomenon of osteoclastogenesis. This inhibitory effect on Ca 2+ oscillation subsequently led to the inhibition of RANKL-induced NFATc1 and c-fos expression after long-term treatment with nicotine. Conclusions We have shown that the activity of nAChRs conveys a marked effect on osteoclastogenesis in mice. Agonists of these receptors inhibited calcium oscillations in osteoclasts and blocked the RANKL-induced activation of c-fos and NFATc1. RANKL-mediated in-vitro osteoclastogenesis was reduced in α7 knockout mice, which was paralleled by increased tibial bone volume in male mice in vivo.

Background Evidence for non-pharmacological interventions in hand osteoarthritis is promising but still scarce. Combined interventions are most likely to best cover the clinical needs of patients with hand osteoarthritis (OA). The aim of this study was to evaluate the effect of a combined, interdisciplinary intervention feasible in both primary and specialist care compared to routine care plus placebo in patients with hand OA. Methods This was a randomised, controlled 2-month trial with a blinded assessor. In the combined-intervention group, rheumatology-trained health professionals from different disciplines delivered a one-session individual intervention with detailed information on functioning, activities of daily living, physical activity, nutrition, assistive devices, instructions on pain management and exercises. Telephone follow up was performed after 4 weeks. The primary outcome was grip strength after 8 weeks. Secondary outcomes were self-reported pain, satisfaction with treatment, health status, two of the Jebsen-Taylor Hand Function subtests and the total score of the Australian/Canadian Hand Osteoarthritis Index (AUSCAN). Statistical significance was calculated by Student’s t test or the Mann-Whitney U test depending on data distribution. Binominal logistic regression models were fitted, with the primary outcome being the dependent and the group allocation being the independent variable. Results There were 151 participating patients (74 in the combined-intervention and 77 in the routine-care-plus-placebo group) with 2-month follow-up attendance of 84% ( n  = 128). Grip strength significantly increased in the combined-intervention group and decreased in the routine-care group (dominant hand, mean 0.03 bar (SD 0.11) versus − 0.03 (SD 0.13), p value = 0.001, baseline corrected values) after 8 weeks. Conclusion The combined one-session individual intervention significantly improved grip strength and self-reported satisfaction with treatment in patients with hand OA. It can be delivered by different rheumatology-trained health professionals and is thus also feasible in primary care. Trial registration ISRCTN registry, ISRCTN62513257 . Registered on 17 May 2012.

Objective Local bone destruction in rheumatic diseases, which often leads to disability and severely reduced quality of life, is almost exclusively mediated by osteoclasts. Therefore, it is important to understand pathways regulating the generation of osteoclasts. Here, we analysed the impact of the Phosphoinositide-3-Kinase (PI3K)/Phosphatase and tensin homolog (PTEN) axis on osteoclast generation and bone biology under basal and inflammatory conditions. Methods We analysed osteoclastogenesis of wildtype (wt) and PTEN−/− cells in vitro and in vivo, pit resorption and qPCR of osteoclasts in vitro. Mice with a myeloid cell-specific deletion of PTEN and wt littermate mice were investigated by bone histomorphometry and clinical and histological assessment in the human tumour necrosis factor (TNF)-transgenic (hTNFtg) arthritis model. Results We show that myeloid-specific PTEN−/− mice display increased osteoclastogenesis in vitro and in vivo compared to wt mice. Loss of PTEN did not affect the generation or survival of osteoclast precursor cells. However, PTEN deficiency greatly enhanced receptor activator of nuclear factor κ-B ligand (RANKL)-induced expression of the master transcription factor of osteoclastogenesis, nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), resulting in markedly increased terminal differentiation of osteoclasts in vitro. We also observed increased osteoclastogenesis under inflammatory conditions in the hTNFtg mouse model of arthritis, where hTNFtg/myeloid-specific PTEN−/− mice displayed enhanced local bone destruction as well as osteoclast formation in the inflamed joints. The extent of synovial inflammation, however, as well as recruitment of osteoclast precursor cells was not different between wt and myeloid-specific PTEN−/− mice. Conclusions These data demonstrate that loss of PTEN and, therefore, sustained PI3-Kinase signalling in myeloid cells especially, elevates the osteoclastogenic potential of myeloid cells, leading to enhanced inflammatory local bone destruction. Therefore, although our study allows no direct translational conclusion since we used a conditional knockout approach, the therapeutic targeting of the PI3-Kinase pathway may be of benefit in preventing structural joint damage.

MicroRNA (miR) 155 has been implicated in the regulation of innate and adaptive immunity as well as autoimmune processes. Importantly, it has been shown to regulate several antiviral responses, but its contribution to the immune response against cytopathic viruses such as vesicular stomatitis virus (VSV) infections is not known. Using transgenic/recombinant VSV expressing ovalbumin, we show that miR-155 is crucially involved in regulating the T helper cell response against this virus. Our experiments indicate that miR-155 in CD4 T cells controls their activation, proliferation, and cytokine production and upon immunization with OVA as well as during VSV viral infection. Using intravital multiphoton microscopy we analyzed the interaction of antigen presenting cells (APCs) and T cells after OVA immunization and found impaired complex formation when using miR-155 deficient CD4 T cells compared to wildtype CD4 T cells . In contrast, miR-155 was dispensable for the maturation of myeloid APCs and for their T cell stimulatory capacity. Our data provide the first evidence that miR-155 is required for efficient CD4 T cell activation during anti-viral defense by allowing robust APC-T cell interaction required for activation and cytokine production of virus specific T cells.

Chronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted joint mobility. In this context, we investigated the impact of the distinct components, including synovial inflammation, bone erosion or cartilage damage, as well as the effect of blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA. We determined CatWalk-assisted gait profiles as objective quantitative measurements of functional impairment. We first determined body-weight-independent gait parameters, including maximum intensity, print length, print width and print area in wild-type mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 – the first clinical signs of arthritis. Moreover, we found further gait changes during chronic disease development, indicating progressive functional impairment in hTNFtg mice. By investigating the association of gait parameters with inflammation-mediated joint pathologies at different time points of the disease course, we found a relationship between gait parameters and the extent of cartilage damage and bone erosions, but not with the extent of synovitis in this chronic model. Next, we observed a significant improvement of functional impairment upon blocking TNF, even at progressed stages of disease. However, blocking TNF did not restore full functionality owing to remaining subclinical inflammation and structural microdamage. In conclusion, CatWalk gait analysis provides a useful tool for quantitative assessment of functional impairment in inflammatory destructive arthritis. Our findings indicate that cartilage damage and bone erosion, but not synovial inflammation, are the most important determinants for progressive functional impairment in this chronic erosive arthritis model.