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Carina Scholtysek,
Julia Katzenbeisser,
He Fu,
Stefan Uderhardt,
Natacha Ipseiz,
Cornelia Stoll,
Mario M Zaiss,
Michael Stock,
Laura Donhauser,
Christina Böhm,
Arnd Kleyer,
Andreas Hess,
Klaus Engelke,
Jean-Pierre David,
Farida Djouad,
Jan Peter Tuckermann,
Béatrice Desvergne,
Georg Schett,
Gerhard Krönke
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ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPARγ has been implicated as major catabolic regulator of bone mass in mice and humans. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPARβ/δ as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPARγ, activation of PPARβ/δ amplified Wnt-dependent and β-catenin-dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPARβ/δ-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPARβ/δ in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPARβ/δ as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.
Nature medicine 03/2013; · 27.14 Impact Factor
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Neng-Yu Lin,
Christian Beyer,
Andreas Gießl,
Trayana Kireva, Carina Scholtysek,
Stefan Uderhardt,
Luis Enrique Munoz,
Clara Dees,
Alfiya Distler,
Stefan Wirtz,
Gerhard Krönke,
Brian Spencer,
Oliver Distler,
Georg Schett,
Jörg H W Distler
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ABSTRACT: OBJECTIVES: Autophagy is a homeostatic process to recycle dispensable and damaged cell organelles. Dysregulation of autophagic pathways has recently been implicated in the pathogenesis of various diseases. Here, we investigated the role of autophagy during joint destruction in arthritis. METHODS: Autophagy in osteoclasts was analysed in vitro and ex vivo by transmission electron microscopy, Western blotting and immunohistochemistry for Beclin1 and Atg7. Small molecule inhibitors, LysMCre-mediated knockout of Atg7 and lentiviral overexpression of Beclin1 were used to modulate autophagy in vitro and in vivo. Osteoclast differentiation markers were quantified by real-time PCR. The extent of bone and cartilage destruction was analysed in human tumour necrosis factor α transgenic (hTNFα tg) mice after adoptive transfer with myeloid specific Atg7-deficient bone marrow. RESULTS: Autophagy was activated in osteoclasts of human rheumatoid arthritis (RA) showing increased expression of Beclin1 and Atg7. TNFα potently induced the expression of autophagy-related genes and activated autophagy in vitro and in vivo. Activation of autophagy by overexpression of Beclin1-induced osteoclastogenesis and enhanced the resorptive capacity of cultured osteoclasts, whereas pharmacologic or genetic inactivation of autophagy prevented osteoclast differentiation. Arthritic hTNFα tg mice transplanted with Atg7(fl/fl)×LysMCre(+) bone marrow cells (BMC) showed reduced numbers of osteoclasts and were protected from TNFα-induced bone erosion, proteoglycan loss and chondrocyte death. CONCLUSIONS: These findings demonstrate that autophagy is activated in RA in a TNFα-dependent manner and regulates osteoclast differentiation and bone resorption. We thus provide evidence for a central role of autophagy in joint destruction in RA.
Annals of the rheumatic diseases 09/2012; · 8.11 Impact Factor
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ABSTRACT: Osteoporosis is characterized by enhanced differentiation of bone-resorbing osteoclasts resulting in a rapid loss of functional trabecular bone. Bone-forming osteoblasts and osteoblast-derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro-osteoclastogenic cytokine RANKL and its natural decoy receptor OPG. By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone-forming osteoblasts and bone-resorbing osteoclasts. By using a system of osteoblast/osteoclast co-cultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast-mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)-induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation and provided complete protection from OVX-induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases. © 2012 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2012; · 6.04 Impact Factor
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Christina Böhm,
Anja Derer,
Roland Axmann,
Ulrike Hillienhoff,
Mario M Zaiss,
Julia Luther,
Christine Zech,
Michael Stock, Carina Scholtysek,
Klaus Engelke,
Andreas Hess,
Jan P Tuckermann,
Georg Schett,
Jean-Pierre David
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ABSTRACT: Tumor necrosis factor (TNF)-α is a key cytokine regulator of bone and mediates inflammatory bone loss. The molecular signaling that regulates bone loss downstream of TNF-α is poorly defined. Here, we demonstrate that inactivating the pro-osteoblastogenic ERK-activated ribosomal S6 kinase RSK2 leads to a drastically accelerated and amplified systemic bone loss in mice ectopically expressing TNF-α [human TNF transgenic (hTNFtg) mice]. The phenotype is associated with a decrease in bone formation because of fewer osteoblasts as well as a drastically increased bone destruction by osteoclasts. The molecular basis of this phenotype is a cell autonomous increased sensitivity of osteoblasts and osteocytes to TNF-induced apoptosis combined with an enhancement of their osteoclast supportive activity. Thus, RSK2 exerts a strong negative regulatory loop on TNF-induced bone loss.
Journal of Cell Science 02/2012; 125(Pt 9):2160-71. · 6.11 Impact Factor
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ABSTRACT: Bone is a dynamic tissue undergoing constant remodelling and repair. Its homeostasis is regulated by a coordinated process executed by bone forming and bone resorbing cells. Apart from being a major component of the locomotive system, bone provides protection for internal organs and represents a main mineral storage. Furthermore, it houses the haematopoietic system and is hence essential for the body's immune response. In turn, the innate and adaptive immune system itself, critically affect bone homeostasis. This is most evident during chronic inflammatory diseases, such as Rheumatoid Arthritis, where bone mass is critically reduced. Recently the field of osteoimmunology, focusing on this crosstalk between the immune system and bone homeostasis, has gained increasing attention. This review will highlight cellular and molecular mechanisms linking the innate and adaptive immune response to bone biology and provide an overview about involved cytokines and cells. Moreover, chronic inflammation and its consequences for bone turnover are discussed.
Inflammation & allergy drug targets. 01/2012; 11(3):188-95.
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Gerhard Krönke,
Nicole Reich, Carina Scholtysek,
Alfiya Akhmetshina,
Stefan Uderhardt,
Pawel Zerr,
Katrin Palumbo,
Veronika Lang,
Clara Dees,
Oliver Distler,
Georg Schett,
Jörg H W Distler
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ABSTRACT: Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc.
To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis.
Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO(-/-) mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO(-/-) mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms
In both models, 12/15-LO(-/-) mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO(-/-) fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects.
These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.
Annals of the rheumatic diseases 01/2012; 71(6):1081-7. · 8.11 Impact Factor
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Mario M Zaiss,
Mariola Kurowska-Stolarska,
Christina Böhm,
Regina Gary, Carina Scholtysek,
Bartosz Stolarski,
James Reilly,
Shauna Kerr,
Neal L Millar,
Thomas Kamradt,
Iain B McInnes,
Padraic G Fallon,
Jean-Pierre David,
Foo Y Liew,
Georg Schett
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ABSTRACT: IL-33 is a new member of the IL-1 family, which plays a crucial role in inflammatory response, enhancing the differentiation of dendritic cells and alternatively activated macrophages (AAM). Based on the evidence of IL-33 expression in bone, we hypothesized that IL-33 may shift the balance from osteoclast to AAM differentiation and protect from inflammatory bone loss. Using transgenic mice overexpressing human TNF, which develop spontaneous joint inflammation and cartilage destruction, we show that administration of IL-33 or an IL-33R (ST2L) agonistic Ab inhibited cartilage destruction, systemic bone loss, and osteoclast differentiation. Reconstitution of irradiated hTNFtg mice with ST2(-/-) bone marrow led to more bone loss compared with the chimeras with ST2(+/+) bone marrow, demonstrating an important endogenous role of the IL-33/ST2L pathway in bone turnover. The protective effect of IL-33 on bone was accompanied by a significant increase of antiosteoclastogenic cytokines (GM-CSF, IL-4, and IFN-γ) in the serum. In vitro IL-33 directly inhibits mouse and human M-CSF/receptor activator for NF-κB ligand-driven osteoclast differentiation. IL-33 acts directly on murine osteoclast precursors, shifting their differentiation toward CD206(+) AAMs via GM-CSF in an autocrine fashion. Thus, we show in this study that IL-33 is an important bone-protecting cytokine and may be of therapeutic benefit in treating bone resorption.
The Journal of Immunology 06/2011; 186(11):6097-105. · 5.79 Impact Factor
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Christina Bohm,
Roland Axmann,
Ulrike Hillienhoff,
Mario M Zaiss,
Christine Zech,
Michael Stock, Carina Scholtysek,
Klaus Engelke,
Andreas Hess,
Jan P Tuckermann,
Georg Schett,
Jean-Pierre David
01/2011;
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Gerhard Krönke,
Stefan Uderhardt,
Kyung-Ah Kim,
Michael Stock, Carina Scholtysek,
Mario M Zaiss,
Cordula Surmann-Schmitt,
Julia Luther,
Julia Katzenbeisser,
Jean-Pierre David,
Shahla Abdollahi-Roodsaz,
Karolyn Tran,
Jessica M Bright,
Minke E Binnerts,
Alfiya Akhmetshina,
Christina Böhm,
Jörg H Distler,
Leo A B Joosten,
Georg Schett,
Arie Abo
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ABSTRACT: During the course of different musculoskeletal diseases, joints are progressively damaged by inflammatory, infectious, or mechanical stressors, leading to joint destruction and disability. While effective strategies to inhibit joint inflammation, such as targeted cytokine-blocking therapy, have been developed during the last decade, the molecular mechanisms of joint damage are still poorly understood. This study was undertaken to investigate the role of the Wnt pathway modulator R-Spondin 1 (RSpo1) in protecting bone and cartilage in a mouse model of arthritis.
Tumor necrosis factor alpha (TNFalpha)-transgenic mice were treated with vehicle or Rspo1. Mice were evaluated for signs of arthritis, and histologic analysis of the hind paws was performed. Moreover, we determined the effect of Rspo1 on Wnt signaling activity and osteoprotegerin (OPG) expression in murine primary osteoblasts.
The secreted Wnt pathway modulator RSpo1 was highly effective in preserving the structural integrity of joints in a TNFalpha-transgenic mouse model of arthritis by protecting bone and cartilage from inflammation-related damage. RSpo1 antagonized the Wnt inhibitor Dkk-1 and modulated Wnt signaling in mouse mesenchymal cells. In osteoblasts, RSpo1 induced differentiation and expression of OPG, thereby inhibiting osteoclastogenesis in vitro. In vivo, RSpo1 promoted osteoblast differentiation and bone formation while blocking osteoclast development, thereby contributing to the integrity of joints during inflammatory arthritis.
Our results demonstrate the therapeutic potential of RSpo1 as an anabolic agent for the preservation of joint architecture.
Arthritis & Rheumatism 08/2010; 62(8):2303-12. · 7.87 Impact Factor
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Gerhard Krönke,
Julia Katzenbeisser,
Stefan Uderhardt,
Mario M Zaiss, Carina Scholtysek,
Gernot Schabbauer,
Alexander Zarbock,
Marije I Koenders,
Roland Axmann,
Jochen Zwerina,
Hans W Baenckler,
Wim van den Berg,
Reinhard E Voll,
Hartmut Kühn,
Leo A B Joosten,
Georg Schett
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ABSTRACT: Eicosanoids are essential mediators of the inflammatory response and contribute both to the initiation and the resolution of inflammation. Leukocyte-type 12/15-lipoxygenase (12/15-LO) represents a major enzyme involved in the generation of a subclass of eicosanoids, including the anti-inflammatory lipoxin A(4) (LXA(4)). Nevertheless, the impact of 12/15-LO on chronic inflammatory diseases such as arthritis has remained elusive. By using two experimental models of arthritis, the K/BxN serum-transfer and a TNF transgenic mouse model, we show that deletion of 12/15-LO leads to uncontrolled inflammation and tissue damage. Consistent with these findings, 12/15-LO-deficient mice showed enhanced inflammatory gene expression and decreased levels of LXA(4) within their inflamed synovia. In isolated macrophages, the addition of 12/15-LO-derived eicosanoids blocked both phosphorylation of p38MAPK and expression of a subset of proinflammatory genes. Conversely, 12/15-LO-deficient macrophages displayed significantly reduced levels of LXA(4), which correlated with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-alpha. Taken together, these results support an anti-inflammatory and tissue-protective role of 12/15-LO and its products during chronic inflammatory disorders such as arthritis.
The Journal of Immunology 09/2009; 183(5):3383-9. · 5.79 Impact Factor
