Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals

Cella, Marina; Buonsanti, Cecilia; Strader, Carey; Kondo, Takayuki; Salmaggi, Andrea; Colonna, Marco

doi:10.1084/jem.20022220

Cited by 205 publications

(192 citation statements)

References 29 publications

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“…Greater levels of TLR ligands suppress the expression of Trem2, thereby abrogating its function. The osteoclast (a close relation to the macrophage) is another cell type that requires Trem2 function (22). We found that in WT and Myd88 Ϫ/Ϫ mice, Trem2 mRNA was induced to its maximum levels at day 2 postinjury, concurrent with peak macrophage accumulation.…”

Section: Efficient Wound Healing Requires Trem2mentioning

confidence: 78%

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Efficient colonic mucosal wound repair requires Trem2 signaling

Seno

Miyoshi²,

Brown³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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239

248

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The colonic epithelial lining undergoes constant replacement, driven by epithelial stem cells in crypts of Lieberkü hn. Stem cells lost because of damage or disease can be replaced by adjacent crypts that undergo fission. The close proximity of an extraordinary number of luminal microbes creates a challenge for this repair process; infection must be prevented while immune system activation and epithelial stem cell genetic damage must be minimized. To understand the factors that modulate crypt/stem cell replacement in the mouse colon, we developed an in vivo acute injury system analogous to punch biopsy of the skin. In contrast to epidermal stem cells, colonic epithelial progenitors did not migrate over the wound bed. Instead, their proliferative expansion was confined to crypts adjacent to wound beds and was delayed to the latter phase of healing. This increased epithelial proliferation was coincident with the infiltration of Trem2 expressing macrophages and increased expression of IL-4 and IL-13 in the wound bed. Interestingly, Trem2 ؊/؊ mice displayed slow and incomplete wound healing of colonic mucosal injuries. We found the latter phase of healing in Trem2 ؊/؊ mice showed a diminished burst of epithelial proliferation, increased expression of IFN-␥ and TNF-␣, diminished expression of IL-4 and IL-13, and increased markers of classical macrophage activation. Ablation of these cytokines in injured WT and Trem2 ؊/؊ mice demonstrated that their expression ultimately determined the rate and nature of wound healing. These studies show that Trem2 signaling is an important pathway to promote healing of wounds in the colon where stem cell replacement is necessary.biopsy injury ͉ epithelium ͉ macrophage ͉ stem cell ͉ wound healing

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Section: Efficient Wound Healing Requires Trem2mentioning

confidence: 78%

“…First, Trem2 is a cell surface receptor (with as yet undetermined ligand) that is specifically induced in macrophages by IL-4/IL-13. Second, Trem2 signaling is important in injury responses (21)(22)(23)(24)(25)(26). In situations where low levels of TLR ligands are present, Trem2 suppresses TLR signaling (23,24).…”

Section: Efficient Wound Healing Requires Trem2mentioning

confidence: 99%

Efficient colonic mucosal wound repair requires Trem2 signaling

Seno

Miyoshi²,

Brown³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

239

248

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“…IL-10, which is increased upon OX40L ligation, at the transition to osteoclast precursors, suppresses RANK-L signaling and human osteoclastogenesis, in part by inhibiting transcription of TREM-2. It is noteworthy that loss-of-function mutations in TREM-2 cause NasuHakola disease, characterized by defective osteoclastogenesis and abnormal bone growth (37).…”

Section: Resultsmentioning

confidence: 99%

“…Bone marrow density, a 3D bone characteristic parameter, was analyzed in 50 consecutive slices. Tb BV (BV/TV), Tb.Th, Tb.N, and Tb.Sp were measured by using the software developed for bone histomorphometry (CT-analyzer software; SkyScan) (37). Serum CTX analysis in WT and ox40l −/− mice with arthritis and WT mice treated with anti-OX40 Fab′PEG was analyzed by using the Mouse C-telopeptide of type II collagen CLIA Kit (Wuhan EIAab Science) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis

Findlay

Danks²,

Madden

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Current therapies to alleviate autoimmune conditions use global strategies that affect large compartments of the immune response. These strategies mop up the excesses of disease without slowing disease progression and carry a significant risk of infection. This article describes the selective inhibition of autoaggressive T cells with the ability to regress established arthritis and reveals an unexpected role for an immune receptor–ligand pair in bone homeostasis.

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“…In the absence of DAP12, several DAP12-associated receptors (DARs), including TREM1 in myeloid cells and Ly49H and Ly49D in NK cells, exhibit significantly decreased surface expression. (7,11) Therefore, we analyzed DAP12 −/− BMMs for expression of TREM2 and found that TREM2 was expressed on the cell surface of BMMs from DAP12-deficient mice maintained in M-CSF for 2 days (Fig. 1D).…”

Section: Combination Of Rankl and M-csf Upregulates Trem2 During In Vmentioning

confidence: 99%

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

Humphrey

Daws

Spusta

et al. 2006

Journal of Bone and Mineral Research

138

146

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Deficiency of the signaling adapter protein DAP12 or its associated receptor TREM2 is associated with abnormal OC development in humans. Here we examine the role of TREM2 in mouse OC development and function, including migration and resorption in vitro. These results provide new evidence that TREM2 regulates OC function independent of its effects on multinucleated OC differentiation.Introduction: TREM2 (triggering receptor expressed in myeloid cells-2) associates with the signaling adapter DAP12 in osteoclasts (OCs). Genetic mutation or deletion of either the TYROBP (DAP12) or TREM2 gene is associated with the human disorder of brain and bone, Nasu-Hakola disease. We and others recently showed the critical requirement for immunoreceptor tyrosine-based activation motif (ITAM) signals through DAP12 and the Fc Receptor ␥ chain (FcR␥) during OC development. Here, we further define the role of TREM2 in OC differentiation and describe a role for TREM2 in OC migration and bone resorption. Materials and Methods:We generated monoclonal anti-mouse TREM2 antibodies (mAb), analyzed preosteoclasts and mature OCs for TREM2 surface expression, and determined the effect of antibody ligation on in vitro OC differentiation, resorption, and migration. TREM2 RNA interference (RNAi) was used to disrupt expression of TREM2 in pre-osteoclasts. Results: Using flow cytometry, our studies reveal that TREM2 is weakly expressed on C57BL/6 bone marrow macrophages (BMMs) and is upregulated during culture with RANKL and macrophage-colony stimulating factor (M-CSF). The expression of TREM2 is unaltered in DAP12-deficient OCs. Using C57BL/6 BMMs or RAW264.7 precursors, anti-TREM2 mAb treatment with RANKL and M-CSF enhances the formation of multinuclear TRACP + OCs compared with control mAb treatment. In contrast, these agents have no effect on DAP12-deficient precursors. Monoclonal Ab blockade of TREM2 on OCs generated from C57BL/6 BMMs results in decreased resorption of artificial calcium-phosphate substrate and dentine. Reduction of TREM2 expression in RAW264.7 cells by RNAi results in loss of OC formation in response to RANKL and M-CSF. Anti-TREM2 cross-linking enhances migration of C57BL/6 OCs and RAW246.7 OCs in response to M-CSF. Conclusions: Our studies indicate that the TREM2 receptor regulates OC multinucleation as well as resorption and migration of mature OCs. Thus, TREM2-DAP12 signals regulate both OC formation and function.

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Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals

Cited by 205 publications

References 29 publications

Efficient colonic mucosal wound repair requires Trem2 signaling

Efficient colonic mucosal wound repair requires Trem2 signaling

OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis

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

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