Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

Nevius, Erin; Pinho, Flavia Oliveira; Dhodapkar, Meera; Jin, Hailing; Nadrah, Kristina; Horowitz, Mark C.; Kikuta, Junichi; Ishii, Masaru; Pereira, João P.

doi:10.1084/jem.20150088

Cited by 52 publications

(44 citation statements)

References 69 publications

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“…Monocytic cells expressing MCSF receptor and that contain osteoclast differentiation potential are also sensitive to FTY720 treatment, but utilize S1PR1 for bone marrow egress (Ishii et al, 2009). This defect in egress, even though partial, is sufficient to accelerate monocyte/osteoclast precursor differentiation into bone resorbing mature osteoclasts (Ishii et al, 2009), likely as a result of increased chemoattraction to osteoclastogenic niches in the endosteum mediated by oxysterols and EBI2 (Nevius, Gomes and Pereira, 2016;Nevius et al, 2015). At later stages of monocytic cell differentiation, inflammatory monocytes are guided out of the bone marrow mostly in a CCR2 dependent manner (Serbina and Pamer, 2006;Shi et al, 2011).…”

Section: Egress From Bone Marrowmentioning

confidence: 99%

A Chemoattractant-Guided Walk Through Lymphopoiesis

Lim

Zehentmeier

Fistonich

et al. 2017

Advances in Immunology

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B lymphocytes develop from hematopoietic stem cells (HSCs) in specialized bone marrow niches composed of rare mesenchymal-lineage stem/progenitor cells (MSPCs) and sinusoidal endothelial cells. These niches are defined by function and location: MSPCs are mostly perisinusoidal cells that together with a small subset of sinusoidal endothelial cells, express stem cell factor (SCF), Interleukin-7 (IL-7), IL-15, and the highest amounts of CXCL12 in bone marrow. Though rare, MSPCs are morphologically heterogeneous, highly reticular, and form a vast cellular network in the bone marrow parenchyma capable of interacting with large numbers of hematopoietic cells. HSCs, downstream multipotent progenitor cells (MPPs) and common lymphoid progenitor cells (CLPs) utilize CXCR4 to fine-tune access to critical short-range growth factors provided by MSPCs for their long-term maintenance and/or multilineage differentiation. In later stages, developing B lymphocytes use CXCR4 to navigate the bone marrow parenchyma, and predominantly Cannabinoid receptor −2 for positioning within bone marrow sinusoids, prior to being released into peripheral blood circulation. In the final stages of differentiation, transitional B cells migrate to the spleen where they preferentially undergo further rounds of differentiation until selection into the mature B cell pool occurs. This bottleneck purges up to 97% of all developing B cells in a peripheral selection process that is heavily controlled not only by the intensity of BCR signaling and access to BAFF, but also by the proper functioning of the B cell motility machinery.

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Section: Egress From Bone Marrowmentioning

confidence: 99%

A Chemoattractant-Guided Walk Through Lymphopoiesis

Lim

Zehentmeier

Fistonich

et al. 2017

Advances in Immunology

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“…For many years it has been appreciated that resorbing bone is chemotactic for osteoclast precursors [134]. Recently, osteoblasts were reported to express oxysterol-synthesis enzymes, namely cholesterol 25 hydroxylase (gene name Ch25h ) and 25-hydroxycholesterol 7-alpha-hydroxylase (gene name Cyp7b1 ) [135]. They also secrete the oxysterol 7a, 25 dihydroxycholesterol (7a, 25-OHC), which acts as a potent chemotractant for the pertussis toxin sensitive Gai protein coupled receptor EBI2 [135].…”

Section: Osteoclast Differentiation Under Homeostasismentioning

confidence: 99%

“…Furthermore, EBI2 is abundantly expressed in murine osteoclast precursors, and its expression increases during osteoclast differentiation [135]. It was reported that EBI2 directs the migration of osteoclast precursors to bone endosteal niches and promotes osteoclastogenesis in vivo [135].…”

Section: Osteoclast Differentiation Under Homeostasismentioning

confidence: 99%

Section: Osteoclast Differentiation Under Homeostasismentioning

confidence: 99%

“…It was reported that EBI2 directs the migration of osteoclast precursors to bone endosteal niches and promotes osteoclastogenesis in vivo [135]. Besides its role in cell positioning at the endosteum, EBI2 signaling also contributes to promote osteoclast precursor motility within bone marrow parenchyma [135], possibly in synergy with CX3CR1 [136]. Importantly, deficiencies in EBI2 or CH25H resulted in similar decreases in osteoclast numbers and increased bone mass in vivo [135], indicating that 7a,25OHC is the main EBI2 ligand controlling osteoclastogenesis and bone mass homeostasis.…”

Section: Osteoclast Differentiation Under Homeostasismentioning

confidence: 99%

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Inflammatory Cell Migration in Rheumatoid Arthritis: A Comprehensive Review

Nevius

Gomes

Pereira

2015

Clinic Rev Allerg Immunol

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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects the joints. Self-reactive B and T lymphocytes cooperate to promote antibody responses against self proteins and are major drivers of disease. T lymphocytes also promote RA independently of B lymphocytes mainly through the production of key inflammatory cytokines, such as IL-17, that promote pathology. While the innate signals that initiate self-reactive adaptive immune responses are poorly understood, the disease is predominantly caused by inflammatory cellular infiltration and accumulation in articular tissues, and by bone erosions driven by bone-resorbing osteoclasts. Osteoclasts are giant multinucleated cells formed by the fusion of multiple myeloid cells that require short-range signals, such as the cytokines MCSF and RANKL, for undergoing differentiation. The recruitment and positioning of osteoclast precursors to sites of osteoclast differentiation by chemoattractants is an important point of control for osteoclastogenesis and bone resorption. Recently, the GPCR EBI2 and its oxysterol ligand 7a, 25 dihydroxycholesterol were identified as important regulators of osteoclast precursor positioning in proximity to bone surfaces, and of osteoclast differentiation under homeostasis. In chronic inflammatory diseases like RA, osteoclast differentiation is also driven by inflammatory cytokines such as TNFa and IL-1, and can occur independently of RANKL. Finally, there is growing evidence that the chemotactic signals guiding osteoclast precursors to inflamed articular sites contribute to disease and are of great interest. Furthering our understanding of the complex osteoimmune cell interactions should provide new avenues of therapeutic intervention for RA.

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NR4A1 Regulates Motility of Osteoclast Precursors and Serves as Target for the Modulation of Systemic Bone Turnover

Scholtysek

Ipseiz

Böhm

et al. 2018

Journal of Bone and Mineral Research

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NR4A1 (Nur77 or NGFI-B), an orphan member of the nuclear receptor superfamily, has been identified as a key regulator of the differentiation and function of myeloid, lymphoid, and mesenchymal cells. The detailed role of NR4A1 in bone biology is incompletely understood. Here, we report a role for NR4A1 as novel factor controlling the migration and recruitment of osteoclast precursors during bone remodeling. Myeloid-specific but not osteoblast-specific deletion of NR4A1 resulted in osteopenia due to an increase in the number of bone-lining osteoclasts. Although NR4A1-deficient osteoclast precursors displayed a regular differentiation into mature osteoclasts, they showed a hyper-motile phenotype that was largely dependent on increased osteopontin expression, suggesting that expression of NR4A1 negatively controlled osteopontin-mediated recruitment of osteoclast precursors to the trabecular bone. Pharmacological activation of NR4A1, in turn, inhibited osteopontin expression and osteopontin-dependent migration of osteoclast precursors resulted in reduced abundance of bone-resorbing osteoclasts in vivo as well as in an ameliorated bone loss after ovariectomy in mice. This study identifies NR4A1 as a crucial player in the regulation of osteoclast biology and bone remodeling and highlights this nuclear receptor as a promising target for therapeutic intervention during the treatment of osteoporosis. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

show abstract

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

Cited by 52 publications

References 69 publications

A Chemoattractant-Guided Walk Through Lymphopoiesis

A Chemoattractant-Guided Walk Through Lymphopoiesis

Inflammatory Cell Migration in Rheumatoid Arthritis: A Comprehensive Review

NR4A1 Regulates Motility of Osteoclast Precursors and Serves as Target for the Modulation of Systemic Bone Turnover

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