IBMS BoneKEy | FEBRUARY 2012 1 Citation: IBMS BoneKEy 9, Article number: 22 (2012) | doi:10.1038/bonekey.2012.13 © 2012 International Bone & Mineral Society All rights reserved 1940-8692/12 www.nature.com/bonekey Increased osteoclast differentiation during postmenopausal osteoporosis, inflammatory arthritis or bone metastases is the leading cause of bone loss. A better understanding of the positive signaling pathways governing osteoclastogenesis, identification of negative regulators that can restrain osteo- clast differentiation and novel modulators of resorption were the central topics at this 2011 American Society of Bone and Mineral Research meeting during the osteoclast sessions. Advances in understanding signals emanated by the receptor activator of nuclear factor- B (RANK) during osteoclastogenesis were made by Liu et al. 1 The requirement for tumor necrosis factor (TNF) receptor-associated factor (TRAF)6 and TRAF6 bind- ing to RANK during osteoclast differentiation is well established. Interestingly, Dr Feng’ s group has identified a novel IVVY motif in the cytoplasmic tail of RANK that has a TRAF-independent role in osteoclast differentiation and function. 2 Now, the pheno- type of mice with a knock-in mutation (IVVY ≥IVAF) that disrupts this motif was presented. 3 Mice homozygous for the AF allele (AF/AF) had increased BV/TV by micro-computed tomograpgy at 8 weeks of age compared with WT controls, whereas hetero- zygous littermates were intermediate. AF/AF mice had decreased numbers of osteoclasts in vivo and in vitro, with concomitant decreases in expression of osteoclast markers such as cathe- psin K, carbonic anhydrase II, TRAP and NFATc1. Interestingly, phosphorylation of I B, ERK and c-Jun N-terminal kinases was intact. Thus, the mechanism by which the IVVY motif regulates osteoclast differentiation, independent of TRAF binding and nuclear factor- B activation, remains to be discovered. New insights into the effects of transforming growth factor-  on RANK ligand (RANKL)-induced osteoclastogenesis were pre- sented by Yasunori Omata in Sakae Tanaka’ s group. 4 ChIP-seq on Smad 2/3 target genes was performed to identify activating histone methylation signatures and responses to transforming growth factor- . Of seven targets identified, Nedd9 was selected for further study. Overexpression of Nedd9 in osteoclast pre- cursors increased differentiation, whereas short hairpin RNA decreased it. Nedd9 - / - mice were generated, and showed an increase in bone mineral density (BMD) in vivo with decreased numbers of osteoclasts. Further work will be needed to demon- strate a mechanism for Nedd9’ s pro-osteoclastogenic activity. Much less is known about negative regulators of osteoclas- togenesis. Baohong Zhao in Lionel Ivashkiv’ s group 5 described several elegant experiments demonstrating a negative regulatory role for Notch/RBP-J during inflammatory osteolysis. Although TNF potently stimulates osteoclastogenesis in vivo during inflam- matory conditions, when added to the precursor cells in vitro, it is very inefficient at inducing osteoclast differentiation. Interestingly, Dr Zhao demonstrated that in the absence of RBP-J, TNF induces robust osteoclastogenesis both in vivo and in vitro, and in a RANKL-independent manner. RBP-J negatively modulates osteoclast differentiation by decreasing Fos activation and pre- venting downregulation of IRF8, a transcriptional repressor that blocks osteoclastogenesis. Activation of RBP-J by transgenic overexpression of the Notch intracellular domain was effective in blocking osteolysis in a model of inflammatory arthritis. Thus, the ability of RBP-J to specifically block inflammatory bone erosion makes it an intriguing therapeutic target. Youridies Vattakuzhi in Nicole Horwood’ s group 6 discussed DUSP1 as another potential brake on inflammatory bone loss. DUSP1 inactivates the mitogen-activated protein kinase p38. Dusp1 - / - osteoclast precursors were particularly sensitive to low doses of RANKL and TNF. When challenged in a collagen- induced arthritis model, Dusp1 - / - mice had enhanced inflam- mation and increased bone loss. Interestingly, Dusp1 - / - mice on a mixed C57/129Sv background developed spontaneous inflammation and bone loss in the digits. Although -catenin signaling in the osteoblast governs osteo- clastogenesis by altering RANKL expression levels, 7 the direct role of -catenin in osteoclasts is a new area of investigation. Millan et al. 8 from the University of Cantabria in Spain showed data indicating that -catenin also suppresses osteoclastogen- esis. Recombinant Wnt3a induced -catenin, reduced osteo- clast differentiation and caused osteoclast apoptosis. Mice depleted of -catenin in the osteoclast lineage (using LysM-Cre) generated more osteoclasts in vitro with macrophage colony- stimulating factor and RANKL, but interestingly, in vivo effects were limited to cortical bone. Cortical thickness was decreased in femurs at 28 weeks, but there were no changes in vertebral trabecular bone, and the number of osteoclasts in sections seemed to be specifically increased on endocortical surfaces. MEETING REPORT Highlights on the osteoclast Roberta Faccio 1 and Deborah V Novack 2 1 Department of Orthopedics, Washington University , St Louis, MO, USA. 2 Bone and Mineral Division, Department of Medicine, Washington University , St Louis, MO, USA. IBMS BoneKEy 9, Article number: 22 (2012) | doi:10.1038/bonekey.2012.13; published online 1 February 2012 Meeting Report from the 33rd Annual Meeting of the American Society for Bone and Mineral Research, San Diego, CA, United States, 16–20 September, 2011.