PURPOSE OF REVIEW: Focal bone loss in inflammatory arthritis begins early in the disease process and can contribute to patient morbidity. Current treatment strategies primarily target suppression of the inflammatory cascade with varying success in limiting the progression of focal bone destruction. This review outlines the current understanding of the mechanisms mediating inflammation-induced focal bone loss in rheumatoid arthritis and other inflammatory arthritides and highlights recent studies in animal models of arthritis that have contributed to our knowledge of this process.
RECENT FINDINGS: Bone-resorbing osteoclasts have been identified as important effector cells in inflammation-induced bone loss in both experimental animal models and human rheumatoid arthritis and psoriatic arthritis. The RANK/RANKL (receptor activator of nuclear factor-kappaB and RANK ligand) pathway has been shown to be essential for osteoclast differentiation in inflammatory arthritis. In addition, in vitro and in vivo studies have demonstrated that many cytokines and growth factors elaborated by inflamed synovial tissues may contribute to osteoclast differentiation and activation.
SUMMARY: Elucidation of the mechanisms mediating osteoclast differentiation and function has identified new pathways for potential targeted therapeutic intervention for focal bone loss in inflammatory arthritis. Challenges in the application of this approach are that therapies targeting the osteoclast would need to be used in combination with effective anti-inflammatory agents, and that pathways mediating osteoclast differentiation and function would need to remain at least partially functional to allow for continued skeletal remodeling.
The molecular mechanisms underlying the putative role of osteopontin in the chronic inflammatory disease rheumatoid arthritis are unclear. A study in a murine model of arthritis now demonstrates that a specific antibody directed against the exposed osteopontin epitope SLAYGLR is capable of preventing inflammatory cell infiltration in arthritic joints.
Histopathologic characterization of bone erosions from patients with rheumatoid arthritis (RA) and studies performed in animal models of inflammatory arthritis provide strong evidence that osteoclasts play an important role in focal marginal and subchondral bone loss in inflammatory arthritis. Much has been learned concerning the factors responsible for the induction and activation of osteoclasts associated with the bone erosions in RA. Therapies that target these osteoclast-inducing factors or other aspects of osteoclast-mediated bone resorption represent potential targets for blocking or at least attenuating bone destruction in RA. The demonstration of the role of the newly described osteoclastogenic factor receptor activator of nuclear factor kappaB ligand in RA synovial tissues and the successful prevention of bone erosions in animal models of arthritis with its inhibitor osteoprotegerin provide hope that specific therapies can be developed for preventing bone and joint destruction in RA, particularly in situations in which disease-modifying agents are ineffective in controlling disease activity.
Rheumatoid arthritis represents an excellent model in which to gain insights into the local and systemic effects of joint inflammation on skeletal tissues. Three forms of bone disease have been described in rheumatoid arthritis. These include: focal bone loss affecting the immediate subchondral bone and bone at the joint margins; periarticular osteopenia adjacent to inflamed joints; and generalized osteoporosis involving the axial and appendicular skeleton. Although these three forms of bone loss have several features in common, careful histomorphometric and histopathological analysis of bone tissues from different skeletal sites, as well as the use of urinary and serum biochemical markers of bone remodeling, provide compelling evidence that different mechanisms are involved in their pathogenesis. An understanding of these distinct pathological forms of bone loss has relevance not only with respect to gaining insights into the different pathological mechanisms, but also for developing specific and effective strategies for preventing the different forms of bone loss in rheumatoid arthritis.
The cases presented illustrate some of the typical (case 1) and less common (case 2) clinical features of beta 2m amyloidosis. The accumulation of beta 2m amyloid in tissues is a potentially severe complication of dialysis-treated chronic renal failure. Beta 2m amyloidosis has been shown to have distinct clinical, radiologic, and pathologic features. The pathogenesis of this condition is not yet clearly understood, and recommendations for the clinical management of these patients at present are limited to recognition of the disease and symptomatic treatment. Further insights into the biology of this disease should lead to new strategies for prevention and treatment.
Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis
Our aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation, and in addition, to uncover the significance of TNF-alpha function in TLR5-mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen-induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, we used anti-TLR5 Ab therapy in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-alpha production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-alpha, because inhibition of both pathways can more strongly impair RA synovial fluid-driven monocyte migration and osteoclast differentiation compared with each factor alone. In preclinical studies, flagellin postonset treatment in CIA and local TLR5 ligation in vivo provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-alpha cascade. Conversely, CIA joint inflammation and bone erosion are alleviated when TLR5 function is blocked. We found that TLR5 and TNF-alpha pathways are interconnected, because TNF-alpha is produced by TLR5 ligation in RA myeloid cells, and anti-TNF-alpha therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct and an indirect mechanism are involved in TLR5-driven RA inflammation and bone destruction.
Induction of bone loss in DBA/1J mice immunized with citrullinated autologous mouse type II collagen in the absence of adjuvant
Joint damage in rheumatoid arthritis (RA) is characterized by cartilage and bone loss resulting in pain, deformity, and loss of joint function. Anti-citrullinated protein antibody (ACPA) has been implicated in RA pathogenesis and predicts radiographical joint damage and clinical severity. Therefore, the purpose of this study was to assess bone loss by micro-CT, histological joint damage, and ACPA levels using a mouse model of RA. Arthritis was induced by immunizing DBA/1 mice with autologous citrullinated type II mouse collagen (CIT-CII) weekly for 4 weeks. Mice immunized with autologous CII served as controls. At week 5, mice were killed, ACPA levels determined, and micro-CT performed to quantitatively analyze bone damage. Micro-CT analysis revealed significant loss of bone density, volume, and surface (p < 0.05) in bone peripheral to the inflamed joints of CIT-CII animals compared to CII controls. Histological staining demonstrated cartilage, proteoglycan, joint collagen, and bone collagen loss in the CIT-CII group compared to CII. Serum ACPA levels were increased (p = 0.03) in the CIT-CII group compared to CII, and these levels were inversely correlated with bone quantity and quality. In this study, we demonstrate that immunization with autologous CIT-CII initiates significant systemic bone and articular cartilage loss in the absence of adjuvant. Significant inverse correlations of circulating ACPA and bone quality/quantity were present. ACPA levels predict the adverse bone morphological changes in this model of early RA.
Role of vascular channels as a novel mechanism for subchondral bone damage at cruciate ligament entheses in osteoarthritis and inflammatory arthritis
OBJECTIVES: The purpose of this work was to test whether normal peri-entheseal vascular anatomy at anterior and posterior cruciate ligaments (ACL and PCL) was associated with distribution of peri-entheseal bone erosion/bone marrow lesions (BMLs) in inflammatory arthritis (IA) and osteoarthritis (OA).
METHODS: Normal microanatomy was defined histologically in mice and by 3 T MRI and histology in 21 cadaveric knees. MRI of 89 patients from the Osteoarthritis Initiative and 27 patients with IA was evaluated for BMLs at ACL and PCL entheses. Antigen-induced arthritis (AIA) in mice was evaluated to ascertain whether putative peri-entheseal vascular regions influenced osteitis and bone erosion.
RESULTS: Vascular channels penetrating cortical bone were identified in knees of non-arthritic mice adjacent to the cruciate ligaments. On MRI of normal cadavers, vascular channels adjacent to the ACL (64% of cases) and PCL (71%) entheses were observed. Histology of 10 macroscopically normal cadaveric specimens confirmed the location of vascular channels and associated subclinical changes including subchondral bone damage (80% of cases) and micro-cyst formation (50%). In the AIA model, vascular channels clearly provided a site for inflammatory tissue entry and osteoclast activation. MRI showed BMLs in the same topographic locations in both patients with early OA (41% ACL, 59% PCL) and IA (44%, 33%).
CONCLUSION: The findings show that normal ACL and PCL entheses have immediately adjacent vascular channels which are common sites of subtle bone marrow pathology in non-arthritic joints. These channels appear to be key determinants in bone damage in inflammatory and degenerative arthritis. already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Hand bone mineral density is associated with both total hip and lumbar spine bone mineral density in post-menopausal women with RA
OBJECTIVE: RA is associated with localized bone loss in the hands, as well as generalized osteoporosis. We evaluated the relationship between hand digital X-ray radiogrammetry BMD (DXR-BMD) and total hip and lumbar spine BMD.
METHODS: We conducted a cross-sectional study of 138 post-menopausal women with RA. The DXR-BMD was calculated based on digitized hand radiographs. Measurements of the total hip and lumbar spine BMD were performed by a DXA-BMD (BMDa) scan. Patient and physician questionnaires and laboratory samples supplied information on relevant covariates. Separate multivariate linear regression models were constructed to determine the cross-sectional relationship between hand DXR-BMD (independent variable) and total hip or lumbar spine BMD (dependent variables).
RESULTS: The cohort comprised women with a median age of 61 years and RA disease duration of 13 years. Seventy-six per cent were either RF and/or anti-cyclic citrullinated peptide (anti-CCP) positive and most had moderate disease activity [median disease activity score-28 joint count (DAS28) 3.7]. Hand DXR-BMD was significantly associated with total hip BMD (beta = 0.61; P < 0.0001) and lumbar spine BMD (beta = 0.62; P < 0.0008) in adjusted models.
CONCLUSIONS: This study suggests that hand DXR-BMD is associated with both the total hip and lumbar spine BMD among post-menopausal women with RA. The relationship between bone loss in the hands and generalized osteoporosis should be further explored in longitudinal studies of patients with RA.
Entheses and bones in spondyloarthritis: 2008 Annual Research and Education Meeting of the Spondyloarthritis Research and Therapy Network (SPARTAN)
The Spondyloarthritis Research and Therapy Network (SPARTAN), founded in 2003 to promote research, education, and treatment of ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA), held its 6th Annual Research and Education Meeting in July 2008 in Cleveland, Ohio, USA. The overall theme of the meeting was entheses and bones in SpA, which included presentations on the anatomy and physiology of the synovial-entheseal complex; bone formation and destruction, and the effect of inflammation on bone; the Th17 axis, HLA-B27, IL23R, and ARTS1; and breakout sessions on epidemiology and registries.
The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis
OBJECTIVE: Among rheumatoid arthritis (RA) patients who have had the disease for 10 years, more than half have focal erosions, and the risk of fracture is doubled. However, there is little information about the potential relationship between focal erosions and bone mineral density (BMD). The aim of this study was to determine whether lower BMD is associated with higher erosion scores among patients with RA.
METHODS: We enrolled 163 postmenopausal women with RA, none of whom were taking osteoporosis medications. Patients underwent dual x-ray absorptiometry at the hip and spine and hand radiography, and completed a questionnaire. The hand radiographs were scored using the Sharp method, and the relationship between BMD and erosions was measured using Spearman's correlation coefficients and adjusted linear regression models.
RESULTS: Patients had an average disease duration of 13.7 years, and almost all were taking a disease-modifying antirheumatic drug. Sixty-three percent were rheumatoid factor (RF) positive. The median modified Health Assessment Questionnaire score was 0.7, and the average Disease Activity Score in 28 joints was 3.8. The erosion score was significantly correlated with total hip BMD (r = -0.33, P < 0.0001), but not with lumbar spine BMD (r = -0.09, P = 0.27). Hip BMD was significantly lower in RF-positive patients versus RF-negative patients (P = 0.02). In multivariable models that included age, body mass index, and cumulative oral glucocorticoid dose, neither total hip BMD nor lumbar spine BMD was significantly associated with focal erosions.
CONCLUSION: Our results suggest that hip BMD is associated with focal erosions among postmenopausal women with RA, but that this association disappears after multivariable adjustment. While BMD and erosions may be correlated with bone manifestations of RA, their relationship is complex and influenced by other disease-related factors.