New Horizons in Orthopaedic Research

Abstract

The report by Nakashima et al.6 in this issue of The Journal and the one by Blaine et al.3 in the October 1997 issue dealt with signal transduction mechanisms in macrophages stimulated by orthopaedic biomaterials. Although these pioneering studies represent initial findings and focus on only a narrow range of possible signaling events, they open new vistas within clinically oriented orthopaedic research. The ultimate aim of this new line of research is to delineate the fundamental cellular mechanisms of periprosthetic osteolysis induced by particulate wear debris and to establish strategies for the development of therapeutic agents to prevent, reverse, or retard this adverse outcome of joint replacement procedures. Furthermore, the study of cellular signal transduction pathways can be applied to numerous areas of orthopaedic research, including the growth and development of cartilage and bone, the pathogenesis of osteoarthritis, fracture-healing, and tumor growth, to name but a few. One of the most important advances in biomedical science in this decade is the identification of intracellular signaling events as part of cellular adaptive responses. These regulatory events are important for mammalian cells to deal with changes in their microenvironment and maintain homeostasis. Cells receive external signals by way of surface membrane receptors, and as a consequence certain amino acids (usually tyrosine, serine, or threonine residues) of the cytoplasmic tail of the receptor become phosphorylated. This initial biochemical event is amplified through a series of protein kinase phosphorylations that in the end trigger a defined set of intracellular adaptive processes, including long-term gene responses. Extracellular compounds in the form of lipids, hormones, growth factors, cytokines, chemokines, counter receptors of other cells, or other cellular mediators can bind to specific cell-surface receptors. These interactions trigger intracellular signal-transduction cascades that result in the modulation of nuclear transcription factor activity. Transcription factors are nuclear …