Abbreviations: DKK1, Dickkopf-1; OPG, osteoprotegerin (also known as TNF receptor superfamily member 11B); RANK, receptor activator of nuclear factor B; RANKL, RANK ligand. The evidence provided by Finzel et al.1 indeed demonstrates that this addition of an anti-TNF agent to methotrexate therapy enhances the likelihood of erosion repair, compared with methotrexate treatment alone. tionrepair of eroded articular bone seems, perplexingly, to occur infrequently. The explanation for Calyculin A this intriguing clinical observation remains to be fully elucidat ed. A report by Finzel now offers insights into the capacity of tradi tional and biologic Calyculin A therapies to promote repair of erosions in patients with RA. Their work suggests that the use of TNF inhibitors techniques us in the right direction in fostering bone formation, but total repair of erosions remains an elusive clinical goal. Finzel and colleagues used high-resolution micro-computed tomography (CT) scanning to better evaluate the impact of RA therapy on repair of articular bone. Erosions detec ted in patients undergoing metho trexate therapy alone, or metho trexate plus an anti-TNF agent (after Calyculin A a minimum of 3 months of stable treatment), were measured for width and depth at base collection and after 1 year of treatment. Using this sensitive CT technique, the authors showed a statistically significant improve ment in the imply depth, but not width, of erosions in patients receiving anti-TNF therapy. By contrast, erosions in patients treated with methotrexate alone showed an increase in mean erosion width and depth, indicating progression. Ero sions that showed a reduction in depth were typically deep lesions, characterized by the presence of sclero tic bone either at baseline and/or at follow-up, indicating that bone repair resulted from new bone formation on endosteal surfaces at the base of the erosions.1 These data in patients with RA follow nicely from studies using mouse models of the disease, which examined the impact of inflammation on osteoblast maturation and bone formation in articular erosions. In these studies, bone surfaces adjacent to invading inflammatory tissue were found to be characterized by impaired bone formation associated with a paucity of mature osteo-blasts, despite the prevalence of immature osteoblast-lineage cells lining the endo steal bone surfaces.2 By contrast, as inflam mation resolved, mature osteo blasts popu lated these surfaces and formed bone, leading to repair of erosions over time.3 Therefore, the degree of local inflammation is likely to be an important factor in de termining erosion repair in RA. Consistent with these observations, previous studies in patients with RA designed to identify repair of erosions by standard radiography have exhibited that erosion repair can occur;4 however, rates of repair are low. In a small cohort of patients with RA treated with standard DMARD therapy, Ideguchi et al.5 exhibited that repair occurred in approximately 10% of patients. Furthermore, repair was recognized primarily in those patients with low disease activity, a finding supported in a more recent study of patients treated with standard therapy.6 Why might we expect patients receiving anti-TNF therapy to experience a better rate of erosion repair than those treated with conventional DMARDs? TNF is usually a pro inflammatory cytokine that contributes significantly to the inflammatory process in RA. Moreover, TNF has an impact on several mechanisms that are directly involved in the erosive process (Physique 1): it increases the expression of the key osteoclast differentiation factor RANKL (receptor activator of nuclear factor B-ligand, also known as TNF ligand super family member 11); it expands the pool of osteoclast pre cursor cells; and it can take action synergisti cally with RANKL to promote osteoclast differ entiation. 7 In addition to promoting osteoclastogenesis and bone resorption, TNF also acts to inhibit bone formation by suppressing osteoblast matura tion through inhibition of the expression of runt-related transcription factor 2, a trans cription factor critical for osteoblastlineage commitment and gene expression, resulting in decreased bone tissue forma mineraliza and tion tion.7 Furthermore, TNF can act on synovial fibroblasts from sufferers with RA to induce the expression of Dickkopf-1, an inhibitor from the Wnt signaling pathway.8 This pathway is vital for osteoblast differentiation, as well as for the bone-forming function of the cells. It comes after that intense treatment of irritation as a result, and specifically, blockade of TNF, could Rabbit Polyclonal to SRF (phospho-Ser77) support the fix of articular erosions. Open up in another window Body 1 TNFa multipotent cytokine in RA. TNF works in proinflammatory signaling pathways inside the joint to donate to irritation, and provides synergistic results on bone tissue turnover: it promotes osteoclast-mediated bone tissue erosion by growing the RANK+ osteoclast precursor cell inhabitants and promoting appearance of RANKL in accordance with OPG; it inhibits osteoblast function and maturation, partly by increasing appearance from the Wnt antagonist DKK1, leading to impaired bone tissue development. Abbreviations: DKK1, Dickkopf-1; OPG, osteoprotegerin (also called TNF receptor superfamily member 11B); RANK, receptor activator of nuclear aspect B; RANKL, RANK ligand..