Bone destruction is a hallmark of chronic rheumatic diseases. Although the role of osteoclasts in bone loss is clearly established, their implication in the inflammatory response has not been investigated despite their monocytic origin. Moreover, specific markers are lacking to characterize osteoclasts generated in inflammatory conditions. Here, we have explored the phenotype of inflammatory osteoclasts and their effect on CD4 T cell responses in the context of bone destruction associated with inflammatory bowel disease. We used the well-characterized model of colitis induced by transfer of naive CD4 T cells into Rag1 mice, which is associated with severe bone destruction. We set up a novel procedure to sort pure osteoclasts generated in vitro to analyze their phenotype and specific immune responses by FACS and qPCR. We demonstrated that osteoclasts generated from colitic mice induced the emergence of TNFα-producing CD4 T cells, whereas those generated from healthy mice induced CD4 FoxP3 regulatory T cells, in an antigen-dependent manner. This difference is related to the osteoclast origin from monocytes or dendritic cells, to their cytokine expression pattern, and their environment. We identified CX CR1 as a marker of inflammatory osteoclasts and we demonstrated that the differentiation of CX CR1 osteoclasts is controlled by IL-17 in vitro. This work is the first demonstration that, in addition to participating to bone destruction, osteoclasts also induce immunogenic CD4 T cell responses upon inflammation. They highlight CX CR1 as a novel dual target for antiresorptive and anti-inflammatory treatment in inflammatory chronic diseases. © 2016 American Society for Bone and Mineral Research.

Our results highlight the osteoclastogenic function of the Th17 TNF-α(+) cells that contribute to bone loss in vivo in IBD.

Osteoclasts promote the formation of the HSC niche by inducing the differentiation of osteoblastic cells from mesenchymal stem cells.

SUMMARY Fatty acid synthase (FAS) is altered in metabolic disorders and cancer. Conventional FAS null mice die in utero so effects of whole body inhibition of lipogenesis following development are unknown. Inducible global knockout of FAS (iFASKO) in mice was lethal due to a disrupted intestinal barrier and leukopenia. Conditional loss of FAS was associated with the selective suppression of granulopoiesis without disrupting granulocytic differentiation. Transplantation of iFASKO bone marrow into wild type mice followed by Cre induction resulted in selective neutrophil depletion but not death. Impaired lipogenesis increased ER stress and apoptosis in neutrophils by preferentially decreasing peroxisome-derived membrane phospholipids containing ether bonds. Inducible global knockout of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, also produced neutropenia. FAS knockdown in neutrophil-like HL-60 cells caused cell loss that was partially rescued by ether lipids. Inhibiting ether lipid synthesis selectively constrains neutrophil development, revealing an unrecognized pathway in immunometabolism.

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• Prolonged inhibition of CXCR4/CXCL12 signaling results in exceptional mobilization along with an expansion of the BM HSPC pool.• Reversible inhibition of the CXCR4/CXCL12 axis may represent a novel strategy to restore damaged BM.Interaction between the chemokine receptor CXCR4 and its chief ligand CXCL12 plays a critical role in the retention and migration of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) microenvironment. In this study, qualitative and quantitative effects of long-term pharmacologic inhibition of the CXCR4/CXCL12 axis on the HSPC compartment were investigated by using 3 structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by administering the antagonists as a subcutaneous continuous infusion for 2 weeks compared to a single bolus injection. A concurrent increase in self-renewing proliferation leading to a twofold to fourfold expansion of the HSPC pool in the BM was observed.The expanded BM showed a distinct repopulating advantage when tested in serial competitive transplantation experiments. Furthermore, major changes within the HSPC niche associated with previously described HSPC expansion strategies were not detected in bones treated with a CXCR4 antagonist infusion. Our data suggest that prolonged but reversible pharmacologic blockade of the CXCR4/CXCL12 axis represents an approach that releases HSPC with efficiency superior to any other known mobilization strategy and may also serve as an effective method to expand the

he is an Advisory Board Member for Cellworks Group, RiverVest Venture Partners, and Arch Oncology. DMM is an employee of and owns equity in Magenta Therapeutics Inc. PGR has stock in Pfizer Inc. PGR and DWG are cofounders of, consultants for, and own equity in Indalo Therapeutics, a company pursuing clinical development of RGD-binding integrin antagonists, but not of antagonists of a α4β1 (VLA4). MPR serves as a consultant for RiverVest Venture Partners, and has received research funding from Amphivena Therapeutics, Novimmmune, and Cantex. MJM receives research funding from Ultragenyx Pharmaceutical Inc. and is the founder and owner of Meyers MedChem Consulting LLC. RFH is currently an employee of Confluence Discovery Technologies. LE has received research funding from MaxCyte Inc. HBB is a coinventor of patent PCT/EP2015/066083 from which he receives royalties and licensing fees; he has received honoraria from Miltenyi,

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