10.2217/17460816.1.1.133 © 2006 Future Medicine Ltd ISSN 1746-0816 Future Rheumatol. (2006) 1(1), 133–146 133 REVIEW Therapeutic approaches in bone pathogeneses: targeting the IKK/NF-κB axis Yousef Abu-Amer † & Roberta Faccio † Author for correspondence Washington University School of Medicine, Department of Orthopedic Surgery-Research, Department of Cell Biology & Physiology, One Barnes Hospital Plaza, Suite 11300 St. Louis, Missouri 63110, USA Tel.: +1 314 362 0335; Fax: +1 314 362 0334; abuamery@wustl.edu Keywords: bone erosion, cytokines, inflammatory arthritis, IKK, NBD, NEMO, NF-κB, osteoclast, osteoprotegerin, RANK, STAT 6 Bone erosion is a major hallmark of rheumatoid arthritis and is executed solely by the bone- resorbing cell, the osteoclast. This cell arises from macrophage precursors and differentiates into the mature polykaryon after stimulation with the receptor activator of NF- κB ligand (RANKL) and macrophage colony-stimulating factor. Osteoclasts are recruited to sites of inflammation, or differentiate at these sites owing to elevated levels of circulating RANKL and other inflammatory cytokines secreted by cells in the inflamed tissue. Recent therapies to combat inflammatory bone erosion have focused on proximal and intracellular signaling molecules to attenuate osteoclast formation and activity. In this review, osteoclast differentiation, activation mechanisms, the role of the NF- κB pathway in inflammatory osteolysis and the relevant intervention approaches are presented briefly. The emphasis of this review will be on the RANKL–RANK–I κB kinase–NF- κB pathway and related antiosteolytic and anti-inflammatory modalities. Inflammatory synovitis and subsequent destruc- tion of joint cartilage and bone are hallmarks of rheumatoid arthritis (RA) [1]. Whereas the destruction of cartilage tissue results primarily from the action of tissue proteinases, focal bone erosion is almost exclusively the result of osteo- clast action. Increased osteoclast activity as is obvious in numerous osteopenic disorders, including RA, leads to increased bone resorption and devastating bone damage. Several studies have established the fact that synovial tissue- residing cells secrete a broad range of inflam- matory cytokines, and factors that directly or indirectly encompass a microenvironment sup- portive of osteoclast recruitment and activation [2,3]. These include interleukin (IL)-1, IL-6, transforming growth factor (TGF)-β, parathyroid hormone (PTH), inducible nitric oxidase synthase (iNOS), cyclooxygenase (COX)-2 and, most notably, members of the tumor necrosis factor (T NF) superfamily of cytokines. T hese latter cytokines include the receptor activator of NF-κB ligand (RANKL) and TNF-α, which activate the Rel/NF-κB fam- ily of transcription factors predominantly [4–7]. T hese transcription factors govern inflammatory and osteolytic processes [8–11] and are thus increasingly considered the centerpiece fueling inflammatory arthritic bone erosion and, as such, the focus for therapeutic intervention. Osteoclast differentiation & activation The bone loss component associated with RA has a devastating impact on human health. T hus, understanding the mechanisms involved in this process is particularly imperative. One key component in this response is the develop- ment and function of the sole bone-resorbing cell, the osteoclast [12]. Osteoclasts are required for skeletal develop- ment, bone resorption and remodeling through- out the lifespan of mammals. Osteoclast differentiation is controlled primarily by the stromal/osteoblast-derived proteins, RANKL and macrophage colony-stimulating factor (M-CSF) [12]. RANKL, a member of the TNF superfamily, binds to its transmembrane receptor, RANK and leads to the differentiation of bone marrow macrophages into multinucleated mature osteoclasts, a process that requires adhesion to the matrix by various cell-associated proteins, termed integrins [13–15]. Several genes, such as PU.1, c- fms (M-CSF receptor), c-fos, RANK and NF-κB (p50, p52 subunits), are critical for osteoclast differentiation. Other gene deletion studies implicated the proto-oncogene c-Src , the proton adenosine triphosphatase (H + -AT Pase) [12,13], nuclear factor for activated T cell (NFAT ) c1, tar- trate-resistant acid phosphatase (T RAP) and cathepsin-k genes [16–18] at later stages of osteoclast activation and function (Figure 1). The principal function of osteoclasts is to resorb bone matrix. T he primary event in this process is acidification of a defined and isolated extracellular resorptive microenvironment. T his critical process is facilitated by adhesion to the matrix and formation of a tightly sealed zone beneath the osteoclast concurrent with polariza- tion of the cell towards bone tissue. T he polariza- tion event is coupled with the translocation of a For reprint orders, please contact: reprints@futuremedicine.com