TREM2, a DAP12‐Associated Receptor, Regulates Osteoclast Differentiation and Function

Department of Medicine, VA Medical Center and University of California, San Francisco, California 94121, USA.
Journal of Bone and Mineral Research (Impact Factor: 6.83). 03/2006; 21(2):237-45. DOI: 10.1359/JBMR.051016
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OCs are the only cells known to resorb bone, and OC resorptive capacity is thought to correlate with the number of OC nuclei present in bones. (18) To explore TREM2-DAP12-mediated regulation of OC resorption, we generated mature OCs using RANKL and M-CSF, and we subsequently examined the effect of TREM2 blockade on bone resorption. TREM2 mAb treatment inhibited resorption by OC in vitro. Anti-TREM2 F(ab′)2 fragments also inhibited resorption, indicating that inhibition of resorption was not caused by activation of OCs by Fc receptors. These results suggest that the anti-TREM2 mAb blocks a potential TREM2 receptor-ligand interaction that is critical for activation of OC resorption in vitro. The low density of OCs in the culture makes it unlikely that TREM2 activation requires interaction with other cells. We have previously shown that TREM2 recognizes several different anionic ligands, functioning like a pattern recognition receptor. (19) Similarly, it is possible that the negatively charged inorganic bone matrix may be sufficient to trigger TREM2 signaling. Thus, antibody blockade may prevent the interaction of TREM2 with the inorganic bone matrix, thereby reducing bone resorption. TREM2 could also interact in cis with a ligand on the same cell or with a secreted, soluble ligand. Alternatively, it remains possible that antibody binding to TREM2 may disrupt complete osteoclast adhesion to bone or bone matrix that is required for functional resorption, which might occur with antibody used in both stimulatory and blocking conditions. Given these results, determining the physiological role of TREM2 blockade on OC activation in vivo is of significant interest.

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Available from: Mary Beth Humphrey, Oct 07, 2015
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    • "Osteoclastogenesis requires cell fusion, cytoskeleton re-organization [7] and the activation of the specific gene sets necessary for bone catabolism. The signaling pathways activated after M-CSF and RANKL induction have been extensively described, and act through TRAF-6 [8,9], immunoreceptor tyrosine-based activation motif (ITAM) [10] adaptors DAP12 [11] and FcRγ [12] associated with their respective receptors, TREM-2 [13] and OSCAR, as well as calcium oscillations [14]. Signals end in the activation of NF-kB, MAPK, and c-Jun, leading to the activation of NFATc1 [15], the master transcription factor of osteoclastogenesis, together with PU.1 and MITF [16], which is already present in the progenitors. "
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    ABSTRACT: DNA methylation is a key epigenetic mechanism for driving and stabilizing cell-fate decisions. Local deposition and removal of DNA methylation are tightly coupled with transcription factor binding, although the relationship varies with the specific differentiation process. Conversion of monocytes to osteoclasts is a unique terminal differentiation process within the hematopoietic system. This differentiation model is relevant to autoimmune disease and cancer, and there is abundant knowledge on the sets of transcription factors involved. Here we focused on DNA methylation changes during osteoclastogenesis. Hypermethylation and hypomethylation changes took place in several thousand genes, including all relevant osteoclast differentiation and function categories. Hypomethylation occurred in association with changes in 5-hydroxymethylcytosine, a proposed intermediate toward demethylation. Transcription factor binding motif analysis revealed an overrepresentation of PU.1, NF-kappaB and AP-1 (Jun/Fos) binding motifs in genes undergoing DNA methylation changes. Among these, only PU.1 motifs were significantly enriched in both hypermethylated and hypomethylated genes; ChIP-seq data analysis confirmed its association to both gene sets. Moreover, PU.1 interacts with both DNMT3b and TET2, suggesting its participation in driving hypermethylation and hydroxymethylation-mediated hypomethylation. Consistent with this, siRNA-mediated PU.1 knockdown in primary monocytes impaired the acquisition of DNA methylation and expression changes, and reduced the association of TET2 and DNMT3b at PU.1 targets during osteoclast differentiation. The work described here identifies key changes in DNA methylation during monocyte-to-osteoclast differentiation and reveals novel roles for PU.1 in this process.
    Genome biology 09/2013; 14(9):R99. DOI:10.1186/gb-2013-14-9-r99 · 10.81 Impact Factor
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    • "Bone-marrow macrophages were isolated as previously described [53]. The transwell migration assay was performed on semi-permeable membranes with pore size of 5 µm (Costar Transwell, Corning, NY). "
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    ABSTRACT: Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme's contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis.
    PLoS ONE 12/2012; 7(12):e52699. DOI:10.1371/journal.pone.0052699 · 3.23 Impact Factor
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    • "For in vivo cell depletion, anti-CD20 (16-0201, eBioscience), anti-CD3 (15-0032, eBioscience), anti-Ly6G (16-5931, eBioscience), Rat IgG2a isotype control (16-4321, eBioscience), and Rat IgG2b isotype control (16-4031, eBioscience) antibodies were purchased. For stimulation of TREM2 on MDMs, anti-rat IgG (102219, Abcam, Cambridge, MA) and anti-TREM2 (MCA4772EL, AbDserotec) or control antibody were prepared as previously described (Humphrey et al., 2006). "
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    ABSTRACT: Jdp2 is an AP-1 family transcription factor that regulates the epigenetic status of histones. Previous in vitro studies revealed that Jdp2 is involved in osteoclastogenesis. However, the roles of Jdp2 in vivo and its pleiotropic functions are largely unknown. Here we generated Jdp2(-/-) mice and discovered its crucial roles not only in bone metabolism but also in differentiation of neutrophils. Jdp2(-/-) mice exhibited osteopetrosis resulting from impaired osteoclastogenesis. Jdp2(-/-) neutrophils were morphologically normal but had impaired surface expression of Ly6G, bactericidal function, and apoptosis. We also found that ATF3 was an inhibitor of neutrophil differentiation and that Jdp2 directly suppresses its expression via inhibition of histone acetylation. Strikingly, Jdp2(-/-) mice were highly susceptible to Staphylococcus aureus and Candida albicans infection. Thus, Jdp2 plays pivotal roles in in vivo bone homeostasis and host defense by regulating osteoclast and neutrophil differentiation.
    Immunity 11/2012; 37(6). DOI:10.1016/j.immuni.2012.08.022 · 21.56 Impact Factor
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