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Growth hormone (GH)-deficiency is usually associated with elevated adiposity, hyperleptinemia, and increased fracture risk. Since leptin is thought to enhance cortical bone formation, we have investigated the contribution of elevated adiposity and hyperleptinemia on femoral strength in rodent models of GH deficiency. Quantification of the transpubertal development of femoral strength in the moderately GH-deficient/hyperleptinemic Tgr rat and the profoundly GH-deficient/hypoleptinemic dw/dw rat revealed that the mechanical properties of cortical bone in these two models were similarly compromised, a 25–30% reduction in failure load being entirely due to impairment of geometric variables. In contrast, murine models of partial (GH antagonist transgenic) and complete (GH receptor-null) loss of GH signaling and elevated adiposity showed an impairment of femoral cortical strength proportionate to the reduction of GH signaling. To determine whether impaired femoral strength is exacerbated by obesity/hyperleptinemia, femoral strength was assessed in dw/dw rats following two developmental manipulations that elevate abdominal adiposity and circulating leptin, neonatal monosodium glutamate (MSG) treatment, and maintenance on an elevated fat diet. The additional impairment of femoral strength following MSG treatment is likely to have resulted from a reduction in residual activity of the hypothalamo-pituitary-GH-IGF-I axis, but consumption of elevated dietary fat, which did not reduce circulating IGF-I, failed to exacerbate the compromised femoral strength in dw/dw rats. Taken together, our data indicate that the obesity and hyperleptinemia usually associated with GH deficiency do not exert a significant influence over the strength of cortical bone.

The North West Business Management Working Group, with members from health and social care agencies, has been responsible for providing data that improves knowledge of the market and supports strategies and initiatives to match need to provision. This paper describes three projects making successful use of its services.

TNF-like protein 1A (TL1A) ligation with death receptor-3 (DR3), a death domain containing member of the tumour necrosis factor receptor superfamily, activates multiple target cell responses. Published genetic and serological data implicate DR3 in rheumatoid arthritis, a chronic inflammatory joint disease. DR3’s function in rheumatoid arthritis has not been established. We question whether; DR3/TL1A activation triggers adverse joint pathology during inflammatory arthritis. We used two murine experimental arthritis models, antigen-induced arthritis (mAIA) and collagen-induced arthritis (mCIA), to study the histological progression of DR3 dependent joint pathology. Osteoclast differentiation assays were performed on both human and mouse macrophages. Osteoclast numbers were quantified in vivo and in vitro by tartrate resistant acid phosphatase staining. In the mAIA model all disease activity indices were significantly reduced in DR3-deficient mice (DR3ko) over age-matched DR3-sufficient wild-type littermate controls. Most striking was the fact that DR3ko were completely protected from the development of the focal bone erosions characteristically seen in mAIA. Add-back experiments with TL1A confirmed that bone pathology was a DR3 specific phenomenon. Our in vitro osteoclast differentiation assays revealed a potential mechanism. We observed heightened DR3-specific osteoclastogenesis in mouse and human macrophage cultures. Osteoclasts are unique in their ability to resorb bone. Finally, we tested the therapeutic efficacy of DR3 antagonism using a TL1A blocking antibody. We found that anti-TL1A significantly reduced the incidence and severity of mCIA. Indeed arthritis was virtually ameliorated at endpoint; all disease activity scores were significantly reduced in anti-TL1A treated mice. Our study reveals the DR3/TL1A axis as an important trigger for adverse joint pathology during inflammatory arthritis and an important regulator of bone turnover. We provide proof-of-concept data which identifies DR3/TL1A antagonism as a potential target to modulate pathology in bone disease and inflammatory arthritis.

Background: Avascular necrosis of the bone (AVN) is a devastating complication in pediatric patients with acute lymphoblastic leukemia (ALL), and articular surface involvement is associated with progressive joint damage. Total body MRI (TBMRI) is a new, non-invasive imaging modality which can identify multiple sites with AVN, with increased STIR signal with corresponding hypointense borders on the T-1 weighted imaging corresponding to AVN lesions. Objectives: To report TBMRI data on 10 patients with pediatric ALL with recent onset of bone pain. Methods: 10 patients (7F, 3M) diagnosed with ALL at median (range) age of 6.2 (3–18) years, and recently developing bone pain were examined with X-ray imaging of the symptomatic region and with TBMRI. TBMRI with coronal T1 and STIR of entire body, with axial T2 fat saturated imaging was performed on each patient at a median (range) of 9 (2–49) months after ALL diagnosis. Results: None of the initial X-ray images revealed abnormal findings. TBMRI showed in 9 of 10 children bone marrow lesions compatible with AVN. In addition to a symptomatic site, all patients had multiple additional lesions. In total, there were a median (range) of 14.5 (5–17)AVN lesions per patient,with amedian (range) of 4.5 (0– 6) lesions per patient at articular surfaces: knee joints (n=8patients); humerus (n=6 patients); femoral heads (n=1 patient); and ankles (n=4 patients). 8/9 patients with articular surface involvement had bilateral lesions. The size varied from small focal lesions to lesions measuring over 95% of the whole transverse diameter of the bone. None of the patients to date have required surgical intervention, but each patient is followed by repeat TBMRI every 6 months. Conclusion: 1. Total body MRI allows early diagnosis of symptomatic as well as clinically non-apparent avascular necrosis (AVN) in pediatric patients with leukemia. 2. TBMRI can be used in planning for medical or surgical therapies.