Schnurri-3 inhibition suppresses bone and joint damage in models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to systemic and articular bone loss by activating bone resorption and suppressing bone formation. Despite current therapeutic agents, inflammation-induced bone loss in RA continues to be a significant clinical problem due to joint deformity and lack of articular and systemic bone repair. Here, we identify the suppressor of bone formation, Schnurri-3 (SHN3), as a potential target to prevent bone loss in RA. SHN3 expression in osteoblast-lineage cells is induced by proinflammatory cytokines. Germline deletion or conditional deletion of Shn3 in osteoblasts limits articular bone erosion and systemic bone loss in mouse models of RA. Similarly, silencing of SHN3 expression in these RA models using systemic delivery of a bone-targeting recombinant adenoassociated virus protects against inflammation-induced bone loss. In osteoblasts, TNF activates SHN3 via ERK MAPK-mediated phosphorylation and, in turn, phosphorylated SHN3 inhibits WNT/ß-catenin signaling and up-regulates RANKL expression. Accordingly, knock-in of a mutation in Shn3 that fails to bind ERK MAPK promotes bone formation in mice overexpressing human TNF due to augmented WNT/ß-catenin signaling. Remarkably, Shn3-deficient osteoblasts are not only resistant to TNF-induced suppression of osteogenesis, but also down-regulate osteoclast development. Collectively, these findings demonstrate SHN3 inhibition as a promising approach to limit bone loss and promote bone repair in RA.

Bone Loss in Rheumatoid Arthritis: Basic Mechanisms and Clinical Implications.

Patients with rheumatoid arthritis (RA) have historically developed progressive damage of articular bone and cartilage, which correlates with disability over time. In addition, these patients are prone to periarticular and systemic bone loss, carrying additional morbidity. In contrast to what is seen in many other rheumatic diseases, the impact of inflammation on bone in RA is uniquely destructive. Loss of articular bone (erosions) and periarticular bone (demineralization) is a result of excessive bone resorption and markedly limited bone formation. There has been tremendous progress in preventing net bone loss in RA with the advent of disease-modifying agents, including biologic agents and small molecules, that both limit inflammation and may have a direct impact on the prevention of cytokine- and antibody-driven osteoclastogenesis. However, repair of existing bone erosions, although feasible, is observed infrequently. Lack of repair is a consequence of suppression of osteoblast function and bone formation by some of the same mechanisms that promote osteoclastogenesis and bone resorption. As new agents are introduced to control inflammation in RA, and novel mechanisms to target synovitis are identified, it may be possible in the future to fully repair damaged bone.

Differential Effects of Inflammation on Bone and Response to Biologics in Rheumatoid Arthritis and Spondyloarthritis.

PURPOSE OF REVIEW: We review the pathways, cytokines, and concepts important to the pathogenesis of bone resorption and formation in rheumatoid arthritis (RA) and spondyloarthritis (SpA). RECENT FINDINGS: Research in bone biology has shed light on the pathogenesis of the joint destruction that occurs in RA and in peripheral SpA. However, understanding the mechanisms behind the bone formation seen in peripheral and axial SpA has been challenging. Mouse models have been used to gain an understanding of key signaling pathways, cytokines and cells regulating inflammation in these diseases. Biologic therapies directed against these targets have been developed to control both inflammation and effects on bone. Although biologic therapies improve joint inflammation in both RA and SpA, leading to a decrease in pain and improving quality of life for patients, the long-term effects of such therapies must also be evaluated by assessing their impact on structural progression. Inhibition of radiographic progression in both RA and peripheral SpA has been easier to demonstrate than in axial SpA. Here, we discuss the similarities and differences among biologic therapies as they pertain to radiographic progression.

Hepatic dysfunction is associated with vitamin D deficiency and poor glycemic control in diabetes mellitus.

BACKGROUND/AIMS: The effect of the rising prevalence of nonalcoholic fatty liver disease on the 25-hydroxylation of pre-vitamin D in the liver, and consequent glycemic control in children with diabetes mellitus is not known. Our aim was to determine whether mild hepatic dysfunction was associated with impaired 25-hydroxylation of pre-vitamin D, and if this vitamin D deficiency was associated with impaired glycemic control in children and adolescents with type 1 diabetes (T1DM) and type 2 diabetes (T2DM). METHODS: We analyzed simultaneously measured HbA1c, ALT, AST, and 25OHD levels and clinical parameters in 121 children and adolescents with T1DM (n=81) and T2DM (n=40). The subjects, ages 11-21 years, all had diabetes of >6 months duration. Multivariate linear regression was used to analyze the associations, while comparisons between subgroups were made using two-tailed Student's t-test. RESULTS: Vitamin D deficiency (25OHD <15 ng/mL (37.5 nmol/L) was more prevalent in T2DM patients (47.5%) compared to T1DM patients (18.5%). Subjects with T2DM had significantly elevated transaminases (AST 39.3 +/- 2.0 vs. 22.4 +/- 1.4, p<0.001; ALT 30.6 +/- 1.8 vs. 18.7 +/- 1.3, p<0.001) compared to TIDM patients, and demonstrated a significant inverse relationship between their HbA1c and 25OHD levels (beta=-0.42, p=0.02), compared to T1DM subjects (beta=-0.06, p=0.62). CONCLUSIONS: The association of elevated ALT with vitamin D deficiency suggests that hepatic dysfunction could impair vitamin D metabolism and negatively impact glycemic control in youth with T2DM.

A role for neutrophils in early enthesitis in spondyloarthritis.

BACKGROUND: Neutrophils are present in the early phases of spondyloarthritis-related uveitis, skin and intestinal disease, but their role in enthesitis, a cardinal musculoskeletal lesion in spondyloarthritis, remains unknown. We considered the role of neutrophils in the experimental SKG mouse model of SpA and in human axial entheses. METHODS: Early inflammatory infiltrates in the axial and peripheral entheseal sites in SKG mice were evaluated using immunohistochemistry and laser capture microdissection of entheseal tissue. Whole transcriptome analysis was carried out using Affymetrix gene array MTA 1.0, and data was analyzed via IPA. We further isolated neutrophils from human peri-entheseal bone and fibroblasts from entheseal soft tissue obtained from the axial skeleton of healthy patients and determined the response of these cells to fungal adjuvant. RESULTS: Following fungal adjuvant administration, early axial and peripheral inflammation in SKG mice was characterized by prominent neutrophilic entheseal inflammation. Expression of transcripts arising from neutrophils include abundant mRNA for the alarmins S100A8 and S100A9. In normal human axial entheses, neutrophils were present in the peri-entheseal bone. Upon fungal stimulation in vitro, human neutrophils produced IL-23 protein, while isolated human entheseal fibroblasts produced chemokines, including IL-8, important in the recruitment of neutrophils. CONCLUSION: Neutrophils with inducible IL-23 production are present in uninflamed human entheseal sites, and neutrophils are prominent in early murine spondyloarthritis-related enthesitis. We propose a role for neutrophils in the early development of enthesitis.

Osteoblast-Osteoclast Communication and Bone Homeostasis.

Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P, SEMA4D, CTHRC1 and C3. Here we review the current knowledge regarding membrane bound- and soluble factors governing cross-talk between osteoblasts and osteoclasts.