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

University of Oslo, Kristiania (historical), Oslo, Norway
Journal of Bone and Mineral Research (Impact Factor: 6.83). 03/2006; 21(2):237-45. DOI: 10.1359/JBMR.051016
Source: PubMed


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
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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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    • "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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