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Osteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases Fabienne Coury, Olivier Peyruchaud, Irma Machuca-Gayet

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Osteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases Fabienne Coury, Olivier Peyruchaud, Irma Machuca-Gayet Osteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases Fabienne Coury, Olivier Peyruchaud, Irma Machuca-Gayet To cite this version: Fabienne Coury, Olivier Peyruchaud, Irma Machuca-Gayet. Osteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases. Frontiers in Immunology, Frontiers, 2019, 10, pp.679. 10.3389/fimmu.2019.00679. hal-02460095 HAL Id: hal-02460095 https://hal.archives-ouvertes.fr/hal-02460095 Submitted on 10 Feb 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. MINI REVIEW published: 03 April 2019 doi: 10.3389/fimmu.2019.00679 Osteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases Fabienne Coury 1,2,3, Olivier Peyruchaud 1,2 and Irma Machuca-Gayet 1,2* 1 INSERM, UMR1033 LYOS, Lyon, France, 2 University Claude Bernard Lyon I, Lyon, France, 3 Department of Rheumatology, Lyon Sud Hospital, Lyon, France Over the past two decades, the field of osteoimmunology has emerged in response to a range of evidence demonstrating the reciprocal relationship between the immune system and bone. In particular, localized bone loss, in the form of joint erosions and periarticular osteopenia, as well as systemic osteoporosis, caused by inflammatory rheumatic diseases including rheumatoid arthritis, the prototype of inflammatory arthritis has highlighted the importance of this interplay. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the joint erosion seen in patients suffering from inflammatory arthritis. Clinical studies have helped to validate the impact of several pathways on osteoclast formation and activity. Essentially, the Edited by: expression of pro-inflammatory cytokines as well as Receptor Activator of Nuclear factor Claudine Blin-Wakkach, κB Ligand (RANKL) is, both directly and indirectly, increased by T cells, stimulating UMR7370 Laboratoire de Physio Médecine Moléculaire (LP2M), France osteoclastogenesis and resorption through a crucial regulator of immunity, the Nuclear Reviewed by: factor of activated T-cells, cytoplasmic 1 (NFATc1). Furthermore, in rheumatoid arthritis, Patrizia D’Amelio, autoantibodies, which are accurate predictors both of the disease and associated University of Turin, Italy Yong-Gil Kim, structural damage, have been shown to stimulate the differentiation of osteoclasts, University of Ulsan College of resulting in localized bone resorption. It is now also evident that osteoblast-mediated Medicine, South Korea bone formation is impaired by inflammation both in joints and the skeleton in rheumatoid Mascha Koenen, University of Ulm, Germany arthritis. This review summarizes the substantial progress that has been made in *Correspondence: understanding the pathophysiology of bone loss in inflammatory rheumatic disease and Irma Machuca-Gayet highlights therapeutic targets potentially important for the cure or at least an alleviation [email protected] orcid.org/0000-0002-3010-9774 of this destructive process. Keywords: inflammatory rheumatic diseases, rheumatoid arthritis, spondyloarthritis, bone erosion, inflammatory Specialty section: bone loss, osteoclast This article was submitted to Inflammation, a section of the journal Frontiers in Immunology INTRODUCTION Received: 08 January 2019 The close relationship between the immune and bone systems has long been noted since Accepted: 12 March 2019 pioneering work on soluble immune cell-derived osteoclast-activating factors performed in the Published: 03 April 2019 early 1970s (1, 2) and was termed osteoimmunology (3). The most significant osteoimmunological Citation: example arose from the observation of osteoclast-mediated bone loss in inflammatory rheumatic Coury F, Peyruchaud O and diseases. Inflammatory rheumatic diseases encompass more than 100 heterogeneous multisystem Machuca-Gayet I (2019) Osteoimmunology of Bone Loss in disorders which can affect joints and lead to disability. However, rheumatoid arthritis (RA) and Inflammatory Rheumatic Diseases. the spondyloarthritis group (SpA) are the most common inflammatory rheumatic diseases that Front. Immunol. 10:679. preferentially affect joints and cause tenderness, swelling, and destruction of joints. Consequently, doi: 10.3389/fimmu.2019.00679 in this review, we will confine the term “inflammatory rheumatic diseases” to these particular Frontiers in Immunology | www.frontiersin.org 1 April 2019 | Volume 10 | Article 679 Coury et al. Bone Loss in Inflammatory Rheumatic Diseases diseases. SpA, also termed “seronegative” as they do not TABLE 1 | Common features and differences in bone loss between SpA and RA. produce rheumatoid factor nor the anti-citrullinated peptide SpA RA antibodies (ACPA) observed in RA, represent a group (AS, PsA, reactive of diseases with common genetic and clinical features, arthritis) including ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis (PsA), and SpA associated with inflammatory Erosions • DIP, PIP joints • MTP, MCP, PIP, and wrist bowel disease. joints RA is considered to be the prototype of destructive • Evenly distributed • Radial sites inflammatory arthritis with bone loss at sites of articular and • Small, or • U-shaped tubule-shaped peri-articular inflammation. SpA also causes inflammation of the • Poorly demarcated • Neatly demarcated axial skeleton and extra-articular entheses leading to not only • Periarticular site • Joint margins bone degradation but also to ectopic bone formation—which • Association with • No association with in some cases can even lead to bony ankylosis of the joint. enthesitis and enthesitis and bone formation bone formation Genetic and experimental evidence has associated the activation Periarticular • absent • May precede bone of IL23-IL17 axis with inflammation and entheseal new bone. osteopenia erosion The ectopic bone formation aspect of SpA will not be discussed Generalized • Axial skeleton • Axial and appendicular further, as herein review focus is restricted to bone loss, formation bone loss skeleton is reviewed elsewhere (4). This dissimilarity in the anatomical • Vertebral fractures • Vertebral and non- sites of bone affected and in bone formation patterns highlights vertebral fractures • Association with ectopic • No association with the differences in pathophysiological mechanisms involved in new bone formation ectopic new these conditions. bone formation Herein, we briefly highlight the key concepts and recent Bone • ↑ Bone resorption • ↑ Bone resorption advances in the osteoimmunology field within the context of remodeling • ↓ bone formation bone loss in inflammatory rheumatic diseases. DIP, distal interphalangeal; MTP, metatarsophalangeal; MCP, metacarpophalangeal; PIP, proximal interphalangeal. RA erosions, Neatly demarcated and located at joint margins where the inflamed synovium is in direct contact with bone, erosions in RA are U- DIFFERENTIAL BONE LOSS IN shaped and observed predominantly in metacarpophalangeal / metatarsophalangeal and proximal interphalangeal joints with a strong preponderance for radial sites; PsA erosion, INFLAMMATORY RHEUMATIC DISEASES Poorly demarcated, smaller in size and depth, Ω or tubule-shaped, and are more evenly distributed. They are located in the periarticular site in proximal and distal interphalangeal Three forms of bone loss have been identified in patients joints and are closely associated with bone formation. with inflammatory rheumatic diseases: localized bone loss with erosion, periarticular osteopenia, and generalized bone generalized bone loss. Radiographic periarticular osteopenia is loss (Table 1). one of the earliest radiological manifestations and may precede Although cortical bone erosion revealed by radiography is bone erosion or joint space narrowing in RA (7). In contrast, commonly considered to be a hallmark of RA, it can also be it appears that there is no periarticular bone loss in early observed in SpA as well as other rheumatic diseases such as PsA (8). gout or osteoarthritis—with a distinct radiographic appearance Secondary systemic osteopenia or osteoporosis involving and location. Erosion begins early in inflammatory rheumatic the axial and appendicular skeleton remote from synovial diseases, even prior to the clinical onset of arthritis: erosion inflammation is an important co-morbidity in inflammatory has been described in ACPA-positive healthy subjects (5). For rheumatic diseases. In effect, the prevalence of densitometric long considered as being less destructive than RA, PsA is osteoporosis in RA patients is increased about two fold compared much more aggressive than previously thought. Essentially, about with the general population and is responsible for a risk 20% of PsA patients develop a mutilating form of arthritis of both vertebral and non-vertebral fractures (9). Although and 40–60% of PsA patients develop erosions in the first 2 patients with SpA have radiographic evidence of ectopic new years of the disease (6). Usually considered to be irreversible, bone formation, many present evidences of marked osteopenia, bone erosion is a key outcome in inflammatory rheumatic and osteoporosis in the spine that
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