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We show that bone marrow (BM) CD34+ progenitor cells from rheumatoid arthritis (RA) patients have the capacity to support spontaneous transformation of peripheral blood B cells. CD34+ cells purified from BM blood from eight RA patients and eight osteoarthritis (OA) patients were expanded with granulocyte/macrophage colony stimulating factor (GM-CSF) for 4–6 weeks. GM-CSF-stimulated BM CD34+ cells from three of eight RA patients, but none from seven OA patients, gave rise to spontaneous transformation of highly purified B cells of Epstein-Barr virus (EBV)-seronegative healthy donors. GM-CSF-stimulated BM CD34+ cells from four of six RA patients and from one of four OA patients also supported the spontaneous transformation of peripheral blood B cells from EBV-seropositive healthy donors. All the transformed B cell lines were positive for EBV-DNA as determined by PCR. Neither GM-CSF-stimulated BM CD34+ cells alone nor highly purified B cells alone gave rise to spontaneously transformed B cell lines. These results suggest that the capacity of BM CD34+ cells to support survival of B cells might contribute to the pathogenesis of RA by sustaining abnormal B cell responses. [ABSTRACT FROM AUTHOR]

This study was conducted to identify bone resorption and anti-inflammatory effects with intermittent cyclical etidronate therapy (ICET) in patients with rheumatoid arthritis, and anti-inflammatory effect of etidronate in vitro. We compared bone mineral density (BMD), urinary deoxypyridinoline (DPD) level, bone alkaline phosphatase (BAP) level and Larsen damage scores between the ICET and the non-ICET groups for 3 years. The levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2), substance P and vascular endothelial growth factor (VEGF) in synovial cells from arthritis models were measured following the addition of etidronate. In the ICET group, BMD and BAP levels increased. Urinary DPD level and the Larsen damage score were significantly lower than that in the non-ICET group. In the in vitro study, the production of IL-6, PGE2, substance P and VEGF were inhibited in a dose-dependent manner. Bone resorption and destruction inhibition effect of etidronate remained for 3 years. In vitro study showed that the production of inflammatory cytokines and an angiogenesis factor were inhibited.

We examined the feasibility of the human immunodeficiency virus (HIV) vector-mediated local expression of angiostatin in the treatment of murine collagen-induced arthritis in a mouse model generated by immunization with bovine type II collagen and Freund's complete adjuvant. The HIV vector containing the murine angiostatin expression unit (HIV-angiostatin) was injected into right knee joints after arthritis development; the HIV vector containing the enhanced green fluorescein protein (EGFP) marker gene (HIV-EGFP) was injected into the left joints. Quantitative histological evaluation demonstrated that synovial cell hyperplasia and pannus formation were significantly reduced in the right knee joints as determined by this protocol. Suppression of radiographical changes in the ipsilateral paws was also observed. These results indicate that the HIV vector-mediated expression of angiostatin efficiently inhibits the progression of collagen-induced arthritis. Angiostatic gene therapy may provide a new approach to the effective treatment of rheumatoid arthritis.

Notch is known as a receptor that controls differentiation or proliferation in various cells and is associated with several diseases. The objective of the present study was to clarify whether human Notch homologues Notch-1, -2, -3, and -4 are expressed in synovium and synoviocytes from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Immunohistochemical staining showed that Notch-1, -2, and -3 were clearly expressed in the synovium from both RA and OA, whereas Notch-4 was only slightly detected. We further performed Western blotting with the same antibodies used in immunohistochemical staining. Notch-1 and -2 were strongly detected in both RA and OA, and the expression of Notch-3 was slightly detected, while there was no Notch-4 expression in both RA and OA synoviocytes. In contrast, all Notch homologues were strongly expressed in the synovium at the developmental stage obtained from the infant. These results indicate that the expression pattern of Notch among synovium from OA and RA patients differed from that of normal subjects.

The expression of the kappa-opioid receptor on human peripheral blood cells (in rheumatoid arthritis cases and normal volunteers) was examined using reverse transcriptase polymerase chain reaction (RT-PCR), and the relationship between its expression and the inflammatory activity or chronic pain in patients with rheumatoid arthritis (RA) was determined. RT-PCR was performed on the peripheral blood cells obtained from 37 patients with RA and 13 healthy volunteers. kappa-Opioid receptor mRNA expression was exhibited on the blood cells of 37% of RA patients (14/ 37) and 54% of healthy volunteers (7/13) , and the levels of expression were lower in the RA patients than in the healthy volunteers. Regarding the relationship between the expression of kappa-opioid receptor mRNA and the symptoms in RA patients, it was noted that the expression of the receptor mRNA was significantly decreased in RA patients in whom erythrocyte sedimentation rate (ESR), Lansbury index, and visual analogue pain scores were high. The kappa-opioid receptor mRNA was expressed on four cell types, namely, T and B cells, macrophages, and natural killer (NK) cells in RA patients; however, it was expressed only on the T and B cells and macrophages (and not on NK cells) in the healthy volunteers. Our findings suggest that the levels of expression of kappa-opioid receptor mRNA were decreased in RA patients in comparison with those in healthy volunteers; and that they were significantly related to the inflammatory activity or chronic pain in the RA patients. The higher the mRNA expression level, the less severe the inflammatory changes of RA. The kappa-opioid receptor may thus play a role in the modulation of nociception and anti-inflammatory changes in chronic inflammatory disorders.