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Cutting Edge: AIM2 and Endosomal TLRs Differentially Regulate Arthritis and Autoantibody Production in DNase II-Deficient Mice

eScholarship@UMMS - Mon, 02/23/2015 - 1:50pm

Innate immune pattern recognition receptors sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. In this study, we use a model of inflammation resulting from accrual of self DNA (DNase II(-/-) type I IFN receptor [Ifnar](-/-)) to understand the role of pattern recognition receptor-sensing pathways in arthritis and autoantibody production. Using triple knockout (TKO) mice deficient in DNase II/IFNaR together with deficiency in either stimulator of IFN genes (STING) or absent in melanoma 2 (AIM2), we reveal central roles for the STING and AIM2 pathways in arthritis. AIM2 TKO mice show limited inflammasome activation and, similar to STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, whereas DNase II(-/-) Ifnar(-/-) mice also deficient in Unc93b, a chaperone required for TLR7/9 endosomal localization, fail to produce autoantibodies to nucleic acids. Collectively, these data support distinct roles for cytosolic and endosomal nucleic acid-sensing pathways in disease manifestations.

Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL

eScholarship@UMMS - Mon, 02/23/2015 - 1:50pm

Receptor activator of nuclear factor-kappaB-ligand (RANKL), encoded by the gene TNFSF11, is required for osteoclastogenesis, and its expression is upregulated in pathologic bone loss. Transcript variants of TNFSF11 messenger RNA (mRNA) have been described that encode a membrane-bound and a putative secreted form of RANKL. We identify a TNFSF11 transcript variant that extends the originally identified transcript encoding secreted RANKL. We demonstrate that this TNFSF11 transcript variant is expressed by the human osteosarcoma cell line, Saos-2, and by both primary human T cells and Jurkat T cells. Of relevance to the production of RANKL in pathologic bone loss, expression of this secreted TNFSF11 transcript is upregulated in Jurkat T cells and primary human T cells upon activation. Furthermore, this transcript can be translated and secreted in Jurkat T cells in vitro and is able to support osteoclast differentiation. Our data highlight the complexity of the TNFSF11 genomic locus, and demonstrate the potential for the expression of alternate mRNA transcripts encoding membrane-bound and secreted forms of RANKL. Implications of alternate mRNA transcripts encoding different RANKL protein isoforms should be carefully considered and specifically examined in future studies, particularly those implicating RANKL in pathologic bone loss.

Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis

eScholarship@UMMS - Mon, 02/23/2015 - 1:50pm

In rheumatoid arthritis (RA), synovial inflammation results in focal erosion of articular bone. Despite treatment attenuating inflammation, repair of erosions with adequate formation of new bone is uncommon in RA, suggesting that bone formation may be compromised at these sites. Dynamic bone histomorphometry was used in a murine model of RA to determine the impact of inflammation on osteoblast function within eroded arthritic bone. Bone formation rates at bone surfaces adjacent to inflammation were similar to those observed in nonarthritic bone; therefore, osteoblast activity is unlikely to compensate for the increased bone resorption at these sites. Within arthritic bone, the extent of actively mineralizing surface was reduced at bone surfaces adjacent to inflammation compared with bone surfaces adjacent to normal marrow. Consistent with the reduction in mineralized bone formation, there was a notable paucity of cells expressing the mid- to late stage osteoblast lineage marker alkaline phosphatase, despite a clear presence of cells expressing the early osteoblast lineage marker Runx2. In addition, several members of the Dickkopf and secreted Frizzled-related protein families of Wnt signaling antagonists were upregulated in arthritic synovial tissues, suggesting that inhibition of Wnt signaling could be one mechanism contributing to impaired osteoblast function within arthritic bone. Together, these data indicate that the presence of inflammation within arthritic bone impairs osteoblast capacity to form adequate mineralized bone, thus contributing to the net loss of bone and failure of bone repair at sites of focal bone erosion in RA.

RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis

eScholarship@UMMS - Mon, 02/23/2015 - 1:50pm

OBJECTIVES: Receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappaB (RANK) in RA at sites of articular bone erosion.

METHODS: Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from bone, four samples contained pannus-bone interface with adjacent synovium and 10 samples contained both synovium remote from bone and pannus-bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of bone erosion.

RESULTS: Cellular expression of RANKL protein was relatively restricted in the bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-bone interface and at sites of subchondral bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from bone but was more limited at sites of bone erosion, especially in regions associated with RANKL expression.

CONCLUSIONS: The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.

TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis

eScholarship@UMMS - Mon, 02/23/2015 - 1:50pm

There is considerable evidence that osteoclasts are involved in the pathogenesis of focal bone erosion in rheumatoid arthritis. Tumor necrosis factor-related activation-induced cytokine, also known as receptor activator of nuclear factor-kappaB ligand (TRANCE/RANKL) is an essential factor for osteoclast differentiation. In addition to its role in osteoclast differentiation and activation, TRANCE/RANKL also functions to augment T-cell dendritic cell cooperative interactions. To further evaluate the role of osteoclasts in focal bone erosion in arthritis, we generated inflammatory arthritis in the TRANCE/RANKL knockout mouse using a serum transfer model that bypasses the requirement for T-cell activation. These animals exhibit an osteopetrotic phenotype characterized by the absence of osteoclasts. Inflammation, measured by clinical signs of arthritis and histopathological scoring, was comparable in wild-type and TRANCE/RANKL knockout mice. Microcomputed tomography and histopathological analysis demonstrated that the degree of bone erosion in TRANCE/RANKL knockout mice was dramatically reduced compared to that seen in control littermate mice. In contrast, cartilage erosion was present in both control littermate and TRANCE/RANKL knockout mice. These results confirm the central role of osteoclasts in the pathogenesis of bone erosion in arthritis and demonstrate distinct mechanisms of cartilage destruction and bone erosion in this animal model of arthritis.

Hospitals Find Big $$ Source: HealthLeaders Media

Headlines from MedPage Today® - Mon, 02/23/2015 - 1:30pm
(MedPage Today) -- Doc shortage in Florida and a new type of care for snowbirds.

TNF Inhibitors May Prevent Uveitis Flare-Ups in AS

Headlines from MedPage Today® - Mon, 02/23/2015 - 1:04pm
(MedPage Today) -- But therapy ineffective for treating inflammatory bowel disease, Crohn's disease.

CardioBreak: PAD Tx Payments, Big $$ for PCSK9 Inhibitors

Headlines from MedPage Today® - Mon, 02/23/2015 - 12:36pm
(MedPage Today) -- Recent developments of interest in cardiovascular medicine.

Saudi Arabia opens top-notch laser lab

news@nature - Mon, 02/23/2015 - 12:21pm

Facility will study biomedical uses at attosecond resolution.

Nature 518 281 doi: 10.1038/518281a

Make the Diagnosis: A 38-Year-Old Man with Sciatica

Headlines from MedPage Today® - Mon, 02/23/2015 - 12:07pm
(MedPage Today) -- Case Study: A thirty-eight-year-old man presented with a four-year history of gradually worsening pain in the lower back and radiation of the pain down both lower limbs. The symptoms began following an automobile accident. A clinical diagnosis of sciatica was made. An MRI of the lumbar spine showed a prolapse of the disc between L4 and L5. An epidural steroid injection temporarily relieved the back pain but did not relieve the radiating pain in the right lower limb. Twelve months later, a repeat MRI revealed a possible lesion posterior to the right acetabulum that could not be evaluated in detail because it was at the edge of the field of view. Clinical evaluation of the hip revealed deep gluteal pain that radiated down the right lower limb and a positive straight-leg-raising test. A detailed MRI of the pelvis, shown here, revealed a 5.8 × 2.2 × 3.8-cm mass deep to the right gluteus maximus and inferior to the piriformis. The tail of the mass extended anteriorly to the posterior aspect of the right labrum. The sciatic nerve (curved arrow in panel d) crossed the anterior aspect of the lesion. (In this image, Ob Int = left obturator internus muscle, F = left femoral head, GMax = left gluteus maximus muscle, and UBl = urinary bladder.)

Vit D Blog: Diabetes vs. Obesity

Headlines from MedPage Today® - Mon, 02/23/2015 - 12:00pm
(MedPage Today) -- Vitamin D levels were lower in diabetic patients than in normoglycemic patients.

Regular Hot, Dry Saunas Boost Heart Health? (CME/CE)

Headlines from MedPage Today® - Mon, 02/23/2015 - 10:00am
(MedPage Today) -- Twice-weekly visits linked to lower CV and mortality risk in Finland.

How Docs Can Impact Kids' Diets

Headlines from MedPage Today® - Mon, 02/23/2015 - 9:31am
(MedPage Today) -- School lunches have improved, but pediatricians can take things a step further.

Early Immunotherapy Helps Kids Beat Peanut Allergy (CME/CE)

Headlines from MedPage Today® - Mon, 02/23/2015 - 9:07am
(MedPage Today) -- Starting treatment in infants and toddlers seems to induce sustained unresponsiveness.

Morning Break: A Few Good Men and a Lot of Viagra; What Sunshine Act?

Headlines from MedPage Today® - Mon, 02/23/2015 - 8:45am
(MedPage Today) -- Health news and commentary from around the Web, gathered by the MedPage Today staff.

Hand Dishwashing Tied to Fewer Allergies for Kids (CME/CE)

Headlines from MedPage Today® - Mon, 02/23/2015 - 8:06am
(MedPage Today) -- Swedish study finds lower rates of asthma, eczema, and allergic conjunctivitis.

Week Ahead: AAAAI, CROI, and GCU, AMA Hits DC, Budget Hearings Start

Headlines from MedPage Today® - Sun, 02/22/2015 - 4:00pm
(MedPage Today) -- The 2015 meeting season kicks into high gear, and the AMA tries again to take The Hill.

10 Questions: Jordan Grumet, MD

Headlines from MedPage Today® - Sun, 02/22/2015 - 3:00pm
(MedPage Today) -- 'Writing has created a shelter from all the trauma of everyday doctoring.'

Rituximab Minus Steroids Tackles IgG4 Disease (CME/CE)

Headlines from MedPage Today® - Sun, 02/22/2015 - 1:00pm
(MedPage Today) -- Most participants saw no disease flares in the 6 months of the study.

Amyloid Seeding May Link Alzheimer's, Diabetes (CME/CE)

Headlines from MedPage Today® - Sun, 02/22/2015 - 11:00am
(MedPage Today) -- Cross-seeding between islet and beta amyloids may link the two disorders.
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