ADAM proteins as therapeutic targets in loosening of total hip replacement implants?

ADAM (A Disintegrin And Metalloprotease) constitute a large and widely expressed family of type I transmembrane proteins with metalloprotease, disintegrin/cysteine-rich, epidermal growth factor-like, transmembrane and cytoplasmic domains1. About 40 ADAM have been identified in different species. ADAM can act as proteolytic enzymes — referred to as “sheddases” — in releasing membrane proteins from the cell surface or cleaving proteins of the extracellular matrix. Substrates of ADAM form a heterogenous group of proteins including cell adhesion molecules, cytokines, and receptors2. There are 2 ways ADAM can modulate cell-cell signalling and cell adhesion: by the shedding of cell adhesion molecules or by direct interaction with cellular integrins via their disintegrin/cysteine-rich domain. Because intracellular domains of ADAM contain protein binding domains such as SH3 or SH2, they are capable of transducing cell signaling. In many diseases, ADAM proteins are considered suitable targets for antiinflammatory therapies3. It is therefore essential to describe the ADAM proteins involved in discrete pathological states. In this issue of The Journal, Dr. Konttinen’s group investigate expression of an ADAM family member, ADAM12, in interface membranes around loosened total hip replacement implants4. Our editorial provides background on the possible roles of ADAM in this process. Aseptic loosening is the major cause of failure in total hip replacement (THR). It is the result of wear-debrisor micromotion-associated inflammatory host response, which can lead to monocyte transmigration, activation of macrophages, formation of multinuclear cells, osteoclasts and foreign body giant cells, and, finally, to massive periprosthetic osteolysis. Inflammation of the synovial-like interface membrane between bone and aseptically loosened prosthesis is considered to play the central role in aseptic loosening5. Typically, synovial-like membranes consist of a combination of fibroblast-like cells, macrophages, and giant cells. Wear particles of the hip replacement implant or micromovement induce transmigration and activation of monocytes, leading to accumulation of macrophages in the synovial membrane. These macrophages are considered to have a dual role: (1) They induce host defense against particles via release of cytokines such as tumor necrosis factor-α (TNF-α) and regulate osteoclast formation, receptor activator of nuclear factor kappa B ligand (RANKL), and macrophage colonystimulating factor (M-CSF)6,7. (2) They are precursor cells for osteoclasts responsible for bone resorption. Thus, aseptic loosening of THR implants depends on the regulated interplay of different cell types and their signaling through the extracellular matrix, and the 2 major events are inflammation and cell-cell fusion. For both events, a functional contribution of ADAM proteins has been described in pathologies of other tissues. Ma, et al analyzed ADAM12 expression in the synovial-like interface membrane around loosened THR implants. ADAM12 was mainly expressed in macrophage-like cells and multinuclear giant cells. Mononuclear ADAM12-expressing cells were detected close to multinuclear ADAM12-expressing cells. Ma, et al describe a strong correlation between ADAM12 expression and multinuclear cells; moreover, in longterm cell cultures, osteoclasts were also formed. Further, M-CSF and RANKL were detected in synovial membranes. Stimulation of monocytes with M-CSF and RANKL led to ADAM12 expression and to fusion in longterm stimulation. ADAM12, originally identified as a myoblast-expressed gene product, was expressed predominantly in skeletal muscle at embryonic and neonatal stages and in bone8. In C2 myoblast cells, ADAM12 was expressed in differentiation-induced myocytes and myotubes. In the same cell line, myotube formation was inhibited by suppression of ADAM12 expression, indicating that ADAM12 is impor-