Involvement of a disintegrin and a metalloproteinase 8 (ADAM8) in osteoclastogenesis and pathological bone destruction.
OBJECTIVE
The eventual role of a disintegrin and a metalloproteinase 8 (ADAM8) in osteoclastogenesis was studied in erosive rheumatoid arthritis (RA) and in vitro.


METHODS
ADAM8 protein and mRNA expression was measured in RA pannus and synovitis and compared to osteoarthritic (OA) synovial membrane. Human monocytes were isolated and stimulated with proinflammatory cytokines and their ADAM8 expression and surface ADAM8 were measured. Human peripheral blood monocytes and RAW 264.7 mouse monocyte/macrophage cells were stimulated to osteclast like-cells, and their expression of ADAM8 and osteoclastic markers (calcitonin receptor, integrin beta 3, cathepsin K, TRAP) were analysed. Transfection and small interfering RNA (siRNA) were used to assess the role of ADAM8 in formation of polykaryons.


RESULTS
Increased numbers of ADAM8 positive cells were shown particularly in the pannus-cartilage/bone junction close or adjoining to TRAP positive multinucleate cells under formation (60 (2)% in pannus, 47 (2)% in synovitis vs 10 (1)% in OA, p<0.001). Human pannus contained high ADAM8 mRNA copy numbers (23 (7) in pannus, 14 (4) in synovitis vs 1.7 (0.3) in OA, p<0.001). Functional studies in vitro disclosed ADAM8 mRNA and protein, which was first converted to a proteolytically active and then to fusion-active form. Gene transfection and siRNA experiments enhanced and inhibited, respectively, expression of osteoclast markers and maturation of multinuclear cells.


CONCLUSIONS
ADAM8 may be involved in bone destruction in RA because it is upregulated in RA pannus adjacent to developing erosions and enhances maturation of osteoclast-like cells.
Ainola
M
M
Department of Medicine, Helsinki University Hospital, Helsinki, Finland.
Li
T-F
TF
Mandelin
J
J
Hukkanen
M
M
Choi
S J
SJ
Salo
J
J
Konttinen
Y T
YT
D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D010010:Osteoclasts / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D018501:Antirheumatic Agents; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051722:ADAM Proteins; C068490:ADAM8 protein, human