Increased expression and processing of ADAM 12 (meltrin-alpha) in osteolysis associated with aseptic loosening of total hip replacement implants

• Published in: Journal of rheumatology 2005-10, Vol.32 (10), p.1943-1950
• Main Authors: Ma, Guofeng, Ainola, Mari, Liljeström, Mikko, Santavirta, Seppo, Poduval, Praseet, Zhao, Desheng, Chen, Tong, Konttinen, Yrjö T
• Format: Article
• Language: English
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAM12 Protein; Aged; Aged, 80 and over; Arthroplasty, Replacement, Hip; Bone Resorption; Carrier Proteins - pharmacology; Cells, Cultured; Female; Giant Cells - metabolism; Hip Prosthesis - adverse effects; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - enzymology; Macrophage Colony-Stimulating Factor - pharmacology; Male; Membrane Glycoproteins - pharmacology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Monocytes - drug effects; Monocytes - enzymology; Osteoclasts - cytology; Osteoclasts - drug effects; Osteolysis - enzymology; Osteolysis - pathology; Prosthesis Failure; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; RNA, Messenger - metabolism
• ISSN: 0315-162X; 1499-2752

OBJECTIVE: To assess the expression and processing of a disintegrin and metalloproteinase, ADAM 12 (meltrin-alpha), in the formation of multinuclear cells. Methods. In situ hybridization, immunohistochemical staining, and Western blotting of interface membrane around loosened total hip replacement implants. Macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) costimulation of human monocytes followed by FACS, immunofluorescence staining, Western blotting, and bone resorption assay. RESULTS: ADAM 12 mRNA-containing mononuclear cells were often seen in a close spatial relationship with ADAM 12-positive multinuclear cells. Morphometric analysis of ADAM 12 disclosed that 53% +/- 2% of all interface cells were ADAM 12-positive compared to 5% +/- 1% in controls (p < 0.001). M-CSF and RANKL were richly present in interface tissue around loosening implants. Upon M-CSF and RANKL costimulation of human monocytes in vitro, the ADAM 12 staining pattern changed over time, and ADAM 12-positive cells formed large mono-, bi-, and multinuclear cells at Day 7 and many multinuclear giant cells and/or osteoclasts at Day 14. Western blot disclosed 90 kDa latent ADAM 12L but also the metalloproteinase-cleaved, fusion-active 60 kDa form transiently just before the burst of fusion. CONCLUSION: ADAM 12, well recognized for participation in cell-cell fusion in myoblast formation, is upregulated and processed upon formation of multinuclear giant cells and osteoclasts. It may play a role in formation of giant cells and osteoclasts around loosened total hip replacement implants.