This study provides strong evidence that TNF-alpha is a key molecule in the control of the inflammatory changes that occur in the RA synovium. In addition, TNF-alpha regulates IL-6 production. However, other inflammatory pathways independent of TNF-alpha may contribute to the bone and cartilage damage seen in RA.

Objective. To elucidate the involvement of the regulatory CD4؉ T cells that produce high levels of interleukin-10 (IL-10) and low levels of IL-4 and IL-2 in the pathogenesis of rheumatoid arthritis (RA), we investigated whether the frequency of this type of CD4؉ T cell subset in peripheral blood lymphocytes (PBL) or synovial lymphocyte infiltrates of patients with RA correlated with disease severity and histologic features in rheumatoid synovium.

The rate of bone formation is largely determined by the number of osteoblasts, which in turn is determined by the rate of replication of progenitors and the life span of mature cells, reflecting the timing of death by apoptosis. However, the exact age-dependent changes of the cellular activity, replicative potential, and life span of osteoblasts have not been investigated to date. Here, we present evidence that the cellular activity, telomere lengths, and replicative life span of osteoblastic cells obtained from juxta-articular bone marrow gradually decrease with the advance of donor age. Recently, telomerase reverse transcriptase (hTERT) has been identified as a human telomerase catalytic subunit. We transfected the gene encoding hTERT into telomerase-negative human osteoblastic cells from donors and osteoblastic cell strain NHOst 54881 cells and showed that expression of hTERT induces telomerase activity in these osteoblastic cells. In contrast to telomerase-negative control cells, which exhibited telomere shortening and senescence after 10 -15 population doublings, telomerase-expressing osteoblastic cells had elongated telomere lengths and showed continued alkaline phosphatase activity and procollagen I C-terminal propeptide (

CONCISE COMMUNICATIONS Increased expression of multidrug resistance of P-glycoprotein on Th1 cells correlates with drug resistance in rheumatoid arthritisAs a mechanism of multidrug resistance (MDR), P-glycoprotein (P-GP) encoded by the MDR1 gene has been known to act as an intracellular energy-dependent transporter that exports MDR-related drugs out of the cells, lowering their intracellular concentration (1). The multidrug-resistant cell lines have an amplified MDR1 gene and overexpression of the encoded P-GP. P-GP is absent in most normal tissues but present in normal tissues with an excretory function, such as adrenal cortex, kidney, intestine, liver, and pancreas. Some patients with rheumatoid arthritis (RA) exhibit resistance to antirheumatic drugs such as disease-modifying antirheumatic drugs (DMARDs). During long-term use of DMARDs, efficacy is either gradually reduced or disappears, and the requirement for switching drugs or adding concomitant drugs is not rare. However, the mechanism responsible for drug resistance to DMARDs is still unknown, although it has been suggested that peripheral blood lymphocytes expressing P-GP are implicated in drug resistance in RA (2).Th1 cells, which produce interferon-␥ (IFN␥), predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory diseases, while Th2 cells, which produce large amounts of interleukin-4 (IL-4), IL-5, and IL-10, are prominent in the pathogenesis of allergic diseases. RA is considered a Th1 disease with a shift toward a Th1-mediated immune response (3,4).We investigated whether P-GP on Th1 or Th2 cells is involved in the response to DMARDs in patients with RA. We recruited 22 patients with early RA who had not previously taken DMARDs. All RA patients were started on regimens of DMARDs. Fourteen received bucillamine (200 mg/day) and 8 received sulfasalazine (1,000 mg/day). Maillefert et al reported that the percentage of lymphocytes expressing P-GP was increased in RA patients treated with prednisolone, and that patients with a high percentage of lymphocytes expressing P-GP could be more resistant to DMARDs and need prednisolone earlier, suggesting that prednisolone may influence the expression of P-GP in the peripheral blood lymphocytes of RA patients (2). To avoid the influence of steroid-induced P-GP on Th1 or Th2 cells, the patients who had previously taken prednisolone or who needed prednisolone during the study period were excluded.Disease activity was assessed from clinical and laboratory responses (pain, tenderness, swelling, patients' and physicians' global assessments, acute-phase protein levels, and disability) at weekly intervals during a 2-month treatment period (5). After 2 months of treatment, RA patients who showed Ͼ30% improvement in Ն5 of 7 measures of disease activity were classified as responders, and those who did not satisfy that definition were classified as nonresponders. We determined the percentages of Th1 or Th2 cells expressing P-GP in peripheral blood CD4ϩ T cells at baseline ...

Our results suggest that osteoblast replicative senescence in periarticular bones occurs more rapidly with aging in RA than in OA patients and contributes to periarticular osteopenia in RA.