Protocolo de valoración de patología articular en paleopatología: estudio de la rodilla en la necrópolis hispanomusulmana de San Nicolás (Murcia, s. XI-XIII)

Trabajo presentado para obtener el Diploma de Estudios Avanzados (DEA)

El sistema mononuclear fagocítico en la progresión de la artritis reumatoide y de la artrosis

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 28 marzo, 2014La artritis reumatoide (AR) y la artrosis (OA) son dos enfermedades reumáticas que comparten mecanismos de lesión tisular, aun siendo de etiopatogenia completamente diferente. Mientras que la sinovitis persistente es el distintivo principal de la AR, hallazgos experimentales y clínicos sugieren que la inflamación sinovial puede estar asociada con la progresión de la OA. Las células del sistema mononuclear fagocítico (SMF) desempeñan múltiples y cruciales funciones en la sinovitis, a pesar de lo cual se desconocen otros aspectos relacionados con su diferenciación y su contribución al daño tisular. Entre ellos, el fenotipo de las células multinucleadas gigantes, ocasionalmente descritas en la sinovitis de la AR y la OA. En este trabajo describimos la elevada frecuencia con la que están presentes estas células, la proximidad tisular de los diversos detritus que probablemente estimulan su diferenciación, así como la asociación con la intensidad de la respuesta inflamatoria. Las células del SMF interaccionan con las diferentes estirpes celulares presentes en la sinovial inflamada, tanto las residentes como las provenientes de la sangre. En este sentido, nos preguntamos si otras células extra-sinoviales pero con participación en la patogenia de ambas artropatías crónicas pudieran tener relación con el SMF. Hemos demostrado que el condrocito puede contribuir, mediante la producción de RANKL por el cartílago y, posterior incremento de la osteoclastogénesis subcondral, a la osteopenia yuxta-articular de la AR. Los factores de riesgo cardiovascular tradicionales, junto con la inflamación sistémica, empeoran la progresión de la arteriosclerosis en la AR. Hemos observado que uno de los componentes del síndrome metabólico, la hipercolesterolemia, también empeora la progresión de la sinovitis reumatoide y la destrucción periarticular erosiva por un incremento de la osteoclastogénesis. En conjunto, estos resultados resaltan la importancia del SMF en la artritis crónica siendo una diana potencial para el tratamiento de la sinovitis en AR y en OA.Rheumatoid arthritis (RA) and osteoarthritis (OA) are two rheumatic diseases sharing tissue lesions mechanisms, despite of their completely different etiopathogenesis. While persistent synovitis is the main hallmark of RA, experimental and clinical findings suggest that synovial inflammation may be associated with OA progression. Mononuclear phagocyte system (MPS) cells take on multiple and crucial functions within the inflamed synovium, however other aspects of its differentiation and contribution to tissue damage remain poorly understood. Among them, multinucleated giant cell (MGC) phenotype which has occasionally been described in rheumatoid and osteoarthritis synovitis. In this study, we first aimed to describe the high frequency with which these cells are present, the close proximity to specific tissue debris probably stimulating its differentiation and its association with the intensity of the inflammatory response. The cells of the MPS interplay with a large variety of synovial cells, both resident and resulting from blood. We wonder whether other extra-synovial cells, also participating in the pathogenesis of both chronic arthropathies, could be associated with the MPS. We have demonstrated how articular chondrocytes may contribute to yuxta-articular bone loss in RA, by producing RANKL in cartilage and subsequently increasing subchondral osteoclastogenesis. The increase of traditional cardiovascular risk factors, along with systemic inflammation, impairs atherosclerosis in RA. We have observed how one of the components of the metabolic syndrome, hyperlipidemia, impairs rheumatoid synovitis progression and periarticular erosive destruction by increasing osteoclastogenesis. Overall results point out the relevance of the MPS in chronic arthritis suggesting that these cells are a potential target for reducing synovitis in RA and OA

Alteraciones de la superficie del cuerpo vertebral en una población medieval de Logroño (s. XI y XII)

X Congreso Nacional de Paleopatología. Univesidad Autónoma de Madrid, septiembre de 200

Characterization of multinucleated giant cells in synovium and subchondral bone in knee osteoarthritis and rheumatoid arthritis

Background: Multinucleated giant cells have been noticed in diverse arthritic conditions since their first description in rheumatoid synovium. However, their role in the pathogenesis of osteoarthritis (OA) or rheumatoid arthritis (RA) still remains broadly unknown. We aimed to study the presence and characteristics of multinucleated giant cells (MGC) both in synovium and in subchondral bone tissues of patients with OA or RA. Methods: Knee synovial and subchondral bone samples were from age-matched patients undergoing total joint replacement for OA or RA, or non-arthritic post mortem (PM) controls. OA synovium was stratified by histological inflammation grade using index tissue sections. Synovitis was assessed by Krenn score. Histological studies employed specific antibodies against macrophage markers or cathepsin K, or TRAP enzymatic assay. Results: Inflamed OA and RA synovia displayed more multinucleated giant cells than did non-inflamed OA and PM synovia. There was a significant association between MGC numbers and synovitis severity. A TRAP negative/cathepsin K negative Langhans-like subtype was predominant in OA, whereas both Langhans-like and TRAP-positive/ cathepsin K negative foreign-body-like subtypes were most commonly detected in RA. Plasma-like and foam-like subtypes also were observed in OA and RA synovia, and the latter was found surrounding adipocytes. TRAP positive/ cathepsin K positive osteoclasts were only identified adjacent to subchondral bone surfaces. TRAP positive osteoclasts were significantly increased in subchondral bone in OA and RA compared to PM controls. Conclusions: Multinucleated giant cells are associated with synovitis severity, and subchondral osteoclast numbers are increased in OA, as well as in RA. Further research targeting multinucleated giant cells is warranted to elucidate their contributions to the symptoms and joint damage associated with arthritis

Pain prediction by serum biomarkers of bone turnover in people with knee osteoarthritis: an observational study of TRAcP5b and cathepsin K in OA

Objectives: To investigate serum biomarkers, tartrate resistant acid phosphatase 5b (TRAcP5b) and cathepsin K, indicative of osteoclastic bone resorption, and their relationship to pain and pain change in knee osteoarthritis (OA). Methods: Sera and clinical data were collected from 129 people (97 with 3-year follow-up) with knee OA from the Prediction of Osteoarthritis Progression (POP) cohort. Knee OA-related outcomes in POP included: WOMAC pain, NHANES I (pain, aching and stiffness), subchondral sclerosis, and radiographically determined tibiofemoral and patellofemoral OA. Two putative osteoclast biomarkers were measured in sera: TRAcP5b and cathepsin K. Medial tibia plateaux were donated at knee arthroplasty for symptomatic OA (n=84) or from 16 post mortem controls from the Arthritis Research UK (ARUK) Pain Centre joint tissue repository. Osteoclasts were stained for TRAcP within the subchondral bone of the medial tibia plateaux. Results: Serum TRAcP5b activity, but not cathepsin K-immunoreactivity, was associated with density of TRAcP-positive osteoclasts in the subchondral bone of medial tibia plateaux. TRAcP-positive osteoclasts were more abundant in people with symptomatic OA compared to controls. Serum TRAcP5b activity was associated with baseline pain and pain change. Conclusions: Our observations support a role for subchondral osteoclast activity in the generation of OA pain. Serum TRAcP5b might be a clinically relevant biomarker of disease activity in OA

The anti-NGF antibody muMab 911 both prevents and reverses pain behaviour and subchondral osteoclast numbers in a rat model of osteoarthritis pain

Objective: Nerve growth factor (NGF) has a pivotal role in peripheral hyperalgesia and inflammation; anti-NGF antibodies attenuate pain responses in inflammatory pain models, and in people with osteoarthritis (OA) or low back pain. The aim of this study was to characterise the peripheral mechanisms contributing to the analgesic effects of anti-NGF antibody treatment in an established model of joint pain, which mimics key clinical features of OA. Design: Effects of preventative vs therapeutic treatment with an anti-NGF antibody (monoclonal antibody 911: muMab 911 (10 mg/kg, s.c.)) on pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWT)), cartilage damage, synovitis and numbers of subchondral osteoclasts were investigated in the monosodium iodoacetate (MIA) model. Potential direct effects of NGF on receptor activator of nuclear factor kappa-B ligand (RANKL) mediated osteoclastogenesis were investigated in cultured human osteoclasts. Results: Intra-articular MIA injection resulted in significant pain behaviour, cartilage damage, synovitis and increased numbers of subchondral osteoclasts. Both preventative and therapeutic treatment with muMab 911 significantly prevented, or reversed, MIA-induced pain behaviour, but did not alter cartilage or synovial pathology quantified at the end of the treatment period. NGF did not facilitate RANKL driven osteoclast differentiation in vitro, but preventative or therapeutic muMab 911 reduced numbers of TRAP positive osteoclasts in the subchondral bone. Conclusions: We demonstrate that anti-NGF antibody treatment attenuates OA pain behaviour despite permitting cartilage damage and synovitis. Indirec

β2 integrins as regulators of dendritic cell, monocyte, and macrophage function

Emerging evidence suggests that the β2 integrin family of adhesion molecules have an important role in suppressing immune activation and inflammation. β2 integrins are important adhesion and signaling molecules that are exclusively expressed on leukocytes. The four β2 integrins (CD11a, CD11b, CD11c, and CD11d paired with the β2 chain CD18) play important roles in regulating three key aspects of immune cell function: recruitment to sites of inflammation; cell–cell contact formation; and downstream effects on cellular signaling. Through these three processes, β2 integrins both contribute to and regulate immune responses. This review explores the pro- and anti-inflammatory effects of β2 integrins in monocytes, macrophages, and dendritic cells and how they influence the outcome of immune responses. We furthermore discuss how imbalances in β2 integrin function can have far-reaching effects on mounting appropriate immune responses, potentially influencing the development and progression of autoimmune and inflammatory diseases. Therapeutic targeting of β2 integrins, therefore, holds enormous potential in exploring treatment options for a variety of inflammatory conditions

Synovitis in osteoarthritis: current understanding with therapeutic implications

Modern concepts of osteoarthritis (OA) have been forever changed by modern imaging phenotypes demonstrating complex and multi-tissue pathologies involving cartilage, subchondral bone and (increasingly recognized) inflammation of the synovium. The synovium may show significant changes, even before visible cartilage degeneration has occurred, with infiltration of mononuclear cells, thickening of the synovial lining layer and production of inflammatory cytokines. The combination of sensitive imaging modalities and tissue examination has confirmed a high prevalence of synovial inflammation in all stages of OA, with a number of studies demonstrating that synovitis is related to pain, poor function and may even be an independent driver of radiographic OA onset and structural progression. Treating key aspects of synovial inflammation therefore holds great promise for analgesia and also for structure modification. This article will review current knowledge on the prevalence of synovitis in OA and its role in symptoms and structural progression, and explore lessons learnt from targeting synovitis therapeutically