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.

IntroductionAn increasing number of studies underline the interactions between the bone and immune systems and have led to the emergence of osteoimmunology. 1,2 Excessive bone resorption is frequently associated with chronic infections and autoimmune and inflammatory diseases. [3][4][5][6] The immune system plays a major role in this process, in particular through activated T cells, which secrete proinflammatory cytokines involved in osteoclastogenesis. 7 However, less is known about the involvement of other immune cells in the control of bone resorption. Dendritic cells (DCs) also play an important role in autoimmune and inflammatory diseases. 8 These cells derive from the same myeloid precursor as osteoclasts (OCLs), and both cell types are modulated by common factors, mainly by receptor activator of NF-B ligand (RANK-L). RANK-L is essential for the differentiation of OCLs, 9 the activity and survival of DCs. 10 These data highlight a potential link between DCs and OCLs.Cells from the myelomonocytic lineage, including DCs, display a high developmental and functional plasticity depending on local factors and stimuli experienced during their differentiation and maturation. 11,12 Although they were considered to be terminally differentiated cells, recent studies have suggested that mature splenic DCs can be influenced by their microenvironment to undergo further differentiation. Splenic stromal cells induce mature DCs to differentiate into regulatory DCs, which differ from mature DCs by their phenotype, their cytokine secretion pattern, and their ability to inhibit T-cell proliferation. 13 Moreover, DCs generated in vitro transdifferentiate into endothelial cells when cultured with tumor-conditioned media 14 or into OCLs when cultured with osteoclastogenic factors. 15,16 Although these in vitro studies revealed the capacity of DCs to transdifferentiate into other cell types under specific conditions, it is not clear yet whether this plasticity takes place in vivo.Osteopetrosis is characterized by an impaired bone resorption because of the absence of OCL formation or activity. 17 In the osteopetrotic oc/oc mouse, differentiated OCLs are present but are unable to resorb bone because of a deletion in the Tcirg1 gene encoding the a3 subunit of the vacuolar ATPase. 18 The a3 protein is responsible for the acidification process necessary for the dissolution of the bone matrix leading to the formation of resorption lacunae. In the absence of a3 expression, the bone marrow of oc/oc mice is filled with numerous and disorganized trabeculae, and osteoclastogenesis is highly increased. 19,20 The consequence of this severe osteopetrotic phenotype is a life span less than 3 weeks. Therefore, the oc/oc mouse provides an appropriate model to assess the in vivo capacity of wild-type precursor cells to give rise to functional OCLs.To assess whether DCs have an osteoclastogenic potential, we purified them from normal mice and cultured them with RANK-L and macrophage-colony stimulating factor (M-CSF). We showed that this treatment a...

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

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IntroductionActivating mutations of growth factor receptors (GFRs) are frequent events in many tumor types. A common theme of such mutations is the acquisition of mutant allele specific imbalance (MASI) either because of copy number-neutral loss of heterozygosity or mutant allele amplification, particularly during disease progression. 1 For example, MASI affects epidermal GFR (EGFR) mutations in lung cancer and glioblastoma, 2 KIT mutations in gastrointestinal tumors, 3 and MPL mutations in myelofibrosis. 4 MASI of activated GFRs may accelerate disease through a simple gene-dosage effect, although it is also possible that loss of the wild-type (WT) protein enhances the impact of the mutant allele, for example, by enhancing formation of mutant homodimers. Although the impact of mutant GFR gene dosage has been modeled in vivo, [5][6][7][8] less is known about the impact of loss of the second WT allele. In the case of activating RET mutations in endocrine neoplasia, deletion of the WT allele occurs in connection with tumor progression, 9,10 although in a mouse model (Ret MEN2B ), hemizygous Ret mutations were not biologically distinct from heterozygous mutations. 11 Although many mutations confer a degree of ligand-independent GFR activation, in vitro studies often observe an additional impact of exogenous ligand. EGFR, 12 platelet-derived GFR, 13 and MET receptor tyrosine kinase mutations 14 are all dependent on their ligands for full transforming activity.FMS-like tyrosine kinase3 (FLT3) is a receptor tyrosine kinase expressed on normal hematopoietic multipotent progenitors 15 and acute leukemia blast cells. 16 Internal tandem duplications (ITDs) within the juxtamembrane domain of FLT3, inducing ligandindependent dimerization and constitutive signaling, occur in ϳ 25% of acute myeloid leukemia (AML). 16 FLT3-ITD is associated with high relapse rate and poor overall survival in AML. 16,17 As with other GFR mutations, MASI at the FLT3 locus in FLT3-ITD ϩ AML is associated with a particularly poor prognosis 18 and occurs because of copy number-neutral loss of heterozygosity with consequent ITD homozygosity. 19 Although MASI is uncommon at diagnosis (ϳ 15% of ITD ϩ cases), it is frequently observed at relapse. 20 Mice heterozygous for an ITD at the endogenous Flt3 locus develop chronic myeloproliferative disease (MPD) with expanded myeloid progenitor cells. 7,21 Importantly, ITD homozygosity results in a more severe MPD phenotype. 7 However, it remains unclear to what degree disease progression only reflects an ITD gene dosage effect and/or whether loss of the WT allele itself might accelerate the phenotype of heterozygous ITDs.Although ITDs clearly induce FLT3 ligand (FL)-independent autophosphorylation of FLT3, 16 addition of exogenous FL to FL-deficient ITD cell lines results in enhanced FLT3 receptor activation. 22 Furthermore, FL increases ITD-induced activation of STAT pathways in vitro, a mechanism proposed to mediate resistance to FLT3 inhibitors. 23 It has recently been suggested that increases in FL levels ...

Multiple myeloma (MM) is one of the most common forms of hematologic malignancy resulting from cancerous proliferation of mature malignant plasma cells (MPCs). But despite the real improvement in therapeutics in the past years, it remains largely incurable. MM is the most frequent cancer to involve bone due to the stimulation of osteoclast (OCL) differentiation and activity. OCLs have a unique capacity to resorb bone. However, recent studies reveal that they are not restrained to this sole function. They participate in the control of angiogenesis, medullary niches, and immune responses, including in MM. Therefore, therapeutic approaches targeting OCLs probably affect not only bone resorption but also many other functions, and OCLs should not be considered anymore only as targets to improve the bone phenotype but also to modulate bone microenvironment. In this review, we explore these novel contributions of OCLs to MM which reveal their strong implication in the MM physiopathology. We also underline the therapeutic interest of targeting OCLs not only to overcome bone lesions, but also to improve bone microenvironment and anti-tumoral immune responses.

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