Altered expression of inflammatory cytokines in primary osteoarthritis by human T lymphotropic virus type I retrovirus infection: a cross-sectional study

Human T cell leukaemia virus type I (HTLV-I) is known to be involved in late-onset chronic polyarthritis as HTLV-I-associated arthropathy. However, it is unclear whether HTLV-I infection could modify the pathophysiology of osteoarthritis (OA). In this study we compared several inflammatory cytokines, such as C-terminal parathyroid hormone-related peptide (C-PTHrP), soluble interleukin-2 receptor (sIL-2R) and interleukin (IL)-6, and an osteo-destruction marker, deoxypyridinoline, in synovial fluid (SF) samples obtained from 22 HTLV-I carriers and 58 control non-carrier patients with OA. These patients were diagnosed clinically and radiographically with primary OA affecting one or both knee joints, and were similar with regard to age, sex and clinical symptoms. We also performed histopathological examination as well as immunohistochemistry of HTLV-I-derived Tax protein in eight synovial tissues taken from carrier patients. C-PTHrP in SF was significantly higher in HTLV-I carriers (287 ± 280 pM) than in non-carriers (69 ± 34 pM), and the concentration in 13 carriers was above the upper range of OA. In HTLV-I carriers, the concentrations of sIL-2R (741 ± 530 IU/ml), IL-6 (55 ± 86 ng/ml) and deoxypyridinoline (3.1 ± 1.8 nM) were higher than in non-carriers (299 ± 303, 2.5 ± 4.0, 0.96 ± 1.0, respectively), and correlated positively with C-PTHrP. C-PTHrP, sIL-2R and IL-6 concentrations in SF positive for IgM antibody against HTLV-I antigen, a marker of persistent viral replication, were higher than of IgM-negative SF. Histologically, five and two synovia showed mild and moderate synovial proliferation with or without some degree of inflammatory reaction, respectively, and could not be distinguished from OA. Tax-positive synoviocytes were observed sparsely in all samples, and often appeared frequently in actively proliferating regions. Our results suggest that although HTLV-I infection does not necessarily worsen the clinical outcome and local synovitis, the virus can potentially modify the pathophysiology of OA by increasing the inflammatory activity in a subset of carrier patients, especially those with IgM antibody. Longitudinal studies are required to assess the association between HTLV-I infection and OA

Effects of monthly intravenous ibandronate on bone mineral density and microstructure in patients with primary osteoporosis after teriparatide treatment: The MONUMENT study

Purpose: To investigate the effects of sequential therapy with monthly intravenous ibandronate on bone mineral density (BMD) and microstructure in patients with primary osteoporosis who received teriparatide treatment. Methods: Sixty-six patients with primary osteoporosis who had undergone teriparatide treatment for more than 12 months (mean 18.6 months) received sequential therapy with 1 mg/month intravenous ibandronate for 12 months. The patients were evaluated using dual-energy X-ray absorptiometry (DXA), quantitative ultrasound, bone turnover markers, and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6 and 12 months after beginning administration. Results: At 12 months after beginning sequential therapy,the bone resorption marker, tartrate-resistant acid phosphatase-5b, decreased by 39.5%, with 82.3% of the patients exhibiting levels within the normal limit. DXA revealed that the BMD of the lumbar spine increased by 3.2%, with 79.0% of the patients exhibiting a response, and 40.3% experiencing an increase in BMD over 5%. HR-pQCT revealed that the cortical thickness of the distal tibia was increased by 2.6%. The cortical area increased by 2.5%, and the buckling ratio (an index of cortical instability) decreased by 2.5%. Most parameters of the trabecular bone showed no significant changes. These changes in the cortical bone were observed in both the distal radius and tibia and appeared beginning 6 months after treatment initiation. Conclusions: Sequential therapy with monthly intravenous ibandronate increased the BMD and improved the cortical bone microstructure of osteoporotic patients who had undergone teriparatide treatment

Dominant-Negative Smad2 Mutants Inhibit Activin/Vg1 Signaling and Disrupt Axis Formation in Xenopus

AbstractSmads are central mediators of signal transduction for the TGFβ superfamily. However, the precise functions of Smad-mediated signaling pathways in early development are unclear. Here we demonstrate a requirement for Smad2 signaling in dorsoanterior axis formation during Xenopus development. Using two point mutations of Smad2 previously identified in colorectal carcinomas, we show that Smad2 ushers Smad4 to the nucleus to form a transcriptional activation complex with the nuclear DNA-binding protein FAST-1 and that the mutant proteins interact normally with FAST-1 but fail to recruit Smad4 into the nucleus. This mechanism of inhibition specifically restricts the dominant-negative activity of these mutants to the activin/Vg1 signaling pathway without inhibiting BMPs. Furthermore, expression of these mutants in Xenopus animal caps inhibits but does not abolish activin and Vg1 induction of mesoderm and in the embryo results in a truncated dorsoanterior axis. These studies define a mechanism through which mutations in Smad2 may block TGFβ-dependent signaling and suggest a critical role for inductive signaling mediated by the Smad2 pathway in Xenopus organizer function