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Increased Expression and Processing of ADAM 12 (Meltrin-a) in Osteolysis Associated with Aseptic Loosening of Total Hip Replacement Implants
GUOFENG MA, MARI AINOLA, MIKKO LILJESTRÖM, SEPPO SANTAVIRTA, PRASEET PODUVAL, DESHENG ZHAO, TONG CHEN, and YRJÖ T. KONTTINEN
ABSTRACT. 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-kB 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. (J Rheumatol 2005;32:1943-50) Key Indexing Terms:
ADAM 12
From the Department of Medicine/Invärtes medicin, Biomedicum, Helsinki University Central Hospital, Helsinki; Department of Anatomy, Institute of Biomedicine, University of Helsinki, Helsinki; Department of Orthopedics and Traumatology, Helsinki University Central Hospital; ORTON Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland; COXA Hospital for Joint Replacement, Tampere, Finland; and All India Institute of Medical Sciences, New Delhi, India. Supported by EVO clinical research grants (TYH 3306; TYH 2267; TYH 3313; TYH 4250), Finska Läkaresällskapet, Stockmann Foundation, and the Centre of Excellence program of the Academy of Finland and Centre for Technological Advancement (TEKES), Invalid Foundation, University of Helsinki Group of Excellence scheme, and the PhD Graduate School on Biomaterials and Tissue Engineering of the Ministry of Education. G.F. Ma, MD, Department of Medicine/Invärtes medicin, Biomedicum, Helsinki University Central Hospital; M. Ainola, MSc; M. Liljeström, MSc, Department of Anatomy, Institute of Biomedicine, University of Helsinki; S. Santavirta, MD, PhD, Department of Orthopedics and Traumatology, Helsinki University Central Hospital; P. Poduval, MSc, All India Institute of Medical Sciences and Department of Medicine/Invärtes medicin, Biomedicum, Helsinki University Central Hospital; D.S. Zhao, MD, Department Medicine/Invärtes medicin, Biomedicum, Helsinki University Central Hospital, ORTON Orthopaedic Hospital of the Invalid Foundation; T. Chen, PhD, Department of Medicine/Invärtes medicin, Biomedicum, Helsinki University Central Hospital; Y.T. Konttinen, MD, PhD, Department of Medicine/Invärtes medicin, Biomedicum, Helsinki University Central Hospital, ORTON Orthopaedic Hospital of the Invalid Foundation, and COXA Hospital for Joint Replacement, Tampere, Finland. Dr. Ma and Ms Ainola contributed equally to this report. Dr. Santavirta is deceased. Address reprint requests to Dr. Y.T. Konttinen, Department of Medicine/Invärtes medicin, PO Box 700, FIN-00029 Helsinki University Hospital, Helsinki, Finland. E-mail: yrjo.konttinen@helsinki.fi Accepted for publication May 9, 2005. |