van der Veen M J, Scheven B A, van Roy J L, Damen C A, Lafeber F P, Bijlsma J W
Department of Rheumatology, University Hospital Utrecht, The Netherlands.
Br J Rheumatol. 1996 Apr;35(4):342-9. doi: 10.1093/rheumatology/35.4.342.
Conflicting data have been published on whether low-dose methotrexate (MTX) treatment of rheumatoid arthritis (RA) is able to slow down radiological joint damage, i.e. retard the destruction of articular cartilage and (subchondral) bone. We studied the effects of MTX on proteoglycan (PG) turnover and interleukin-1 (IL-1)- and RA mononuclear cell (RA-MNC)-induced cartilage damage in human articular cartilage tissue cultures, and the effects of MTX on basal and RA-MNC-influenced proliferation and differentiation of osteoblasts in cultures of human bone-derived osteoblasts. MTX exerted no direct effect on cartilage nor did MTX influence IL-1- or RA-MNC-induced cartilage damage, despite strong suppression of basal as well as mitogen- and antigen-induced RA-MNC proliferation. MTX induced strong inhibition of osteoblast proliferation, but did not significantly interfere with osteoblast differentiation (i.e. alkaline phosphatase activity). RA-MNC-enhanced proliferation and differentiation of osteoblasts were abolished by MTX. These results suggest that if MTX is able to induce retardation of radiological progression in RA, this is not based on an initial direct effect of MTX on cartilage as measured by PG turnover, nor on an initial inhibition of IL-1- or RA-MNC-induced cartilage damage. However, longstanding MTX-induced inhibition of RA-MNC proliferation may lead to reduction of the catabolic activity involved in cartilage destruction. On the other hand, long-term inhibition of osteoblast proliferation may eventually lead to decreased bone formation and osteopenia. Whether this will turn out to be a problem of clinical importance in the treatment of RA has to be established.
关于低剂量甲氨蝶呤（MTX）治疗类风湿关节炎（RA）是否能够减缓放射学关节损伤，即延缓关节软骨和（软骨下）骨的破坏，已有相互矛盾的数据发表。我们研究了MTX对人关节软骨组织培养中蛋白聚糖（PG）周转以及白细胞介素-1（IL-1）和RA单核细胞（RA-MNC）诱导的软骨损伤的影响，以及MTX对人骨源性成骨细胞培养中基础和成骨细胞受RA-MNC影响的增殖和分化的作用。MTX对软骨没有直接作用，也不影响IL-1或RA-MNC诱导的软骨损伤，尽管它能强烈抑制基础以及有丝分裂原和抗原诱导的RA-MNC增殖。MTX强烈抑制成骨细胞增殖，但对成骨细胞分化（即碱性磷酸酶活性）没有显著干扰。MTX消除了RA-MNC增强的成骨细胞增殖和分化。这些结果表明，如果MTX能够在RA中诱导放射学进展延缓，这并非基于MTX对PG周转所测量的软骨的初始直接作用，也不是基于对IL-1或RA-MNC诱导的软骨损伤的初始抑制。然而，MTX长期诱导的RA-MNC增殖抑制可能导致参与软骨破坏的分解代谢活性降低。另一方面，成骨细胞增殖的长期抑制最终可能导致骨形成减少和骨质减少。这在RA治疗中是否会成为具有临床重要性的问题还有待确定。
