Methotrexate in the treatment of rheumatoid arthritis. I. In vitro effects on cells of the osteoblast lineage.
OBJECTIVE
Low-dose methotrexate (MTX) is often used in the treatment of rheumatoid arthritis (RA). To be effective, treatment must be long-term, and there are concerns that MTX may impair bone formation in a population already predisposed to osteoporosis. The purpose of this investigation was to determine the direct effects of MTX at clinically relevant doses on the growth and differentiation of human cells of the osteoblast (bone-forming) lineage.


METHODS
Cells derived from the marrow stroma (BMSC) and trabecular surfaces [human bone-derived cells (HBDC)] of adult ribs were cultured in the absence or presence of MTX (1-1000 nM). To promote the differentiation and further maturation of cells of the osteoblast lineage, one half of the cultures were treated additionally with 10 nM dexamethasone (Dx).


RESULTS
In cultures of BMSC, treatment with MTX (+/-Dx) did not affect the total number of colonies that formed or the expression of the developmental markers STRO-1 and alkaline phosphatase (AP). At concentrations > or =10 nM, however, there was a statistically significant reduction in the number of cells harvested at the end of primary culture. In cultures of HBDC, treatment with MTX (in the presence of Dx) did not affect cell number or the expression of AP.


CONCLUSIONS
At concentrations > or =10 nM, treatment with MTX inhibits the proliferation of primitive marrow stromal cells, but not their ability to undergo osteogenic differentiation. The proliferation and further maturation of cells of the osteoblast lineage is not affected by treatment with MTX. These findings are reassuring for clinicians using MTX in the treatment of RA.
Minaur
N J
NJ
Bone Research Group, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Jefferiss
C
C
Bhalla
A K
AK
Beresford
J N
JN
D036541:ADP-ribosyl Cyclase; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000378:metabolism; D015703:Antigens, CD; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D015415:Biomarkers / Q000032:analysis; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D012272:Ribs / Q000166:cytology; D013234:Stem Cells / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
D015703:Antigens, CD; D018501:Antirheumatic Agents; D015415:Biomarkers; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D003907:Dexamethasone; D000469:Alkaline Phosphatase; D036541:ADP-ribosyl Cyclase; C087521:ADP-ribosyl cyclase 2; D008727:Methotrexate