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Monocyte-Specific Knockout of C/ebp? Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebp? in Osteoclast Differentiation and Function.

ABSTRACT: CCAAT/enhancer-binding protein ? (C/ebp?) is critical for osteoclastogenesis by regulating osteoclast (OC) lineage commitment and is also important for OC differentiation and function in vitro. However, the role of C/ebp? in postnatal skeletal development has not been reported owing to lethality in C/ebp?-/- mice from hypoglycemia within 8 hours after birth. Herein, we generated conditional knockout mice by deleting the C/ebp? gene in monocyte via LysM-Cre to examine its role in OC differentiation and function. C/ebp?f/f LysM-Cre mice exhibited postnatal osteopetrosis due to impaired osteoclastogenesis, OC lineage priming defects, as well as defective OC differentiation and activity. Furthermore, our ex vivo analysis demonstrated that C/ebp? conditional deletion significantly reduced OC differentiation, maturation, and activity while mildly repressing macrophage development. At the molecular level, C/ebp? deficiency significantly suppresses the expressions of OC genes associated with early stages of osteoclastogenesis as well as genes associated with OC differentiation and activity. We also identified numerous C/ebp? critical cis-regulatory elements on the Cathepsin K promoter that allow C/ebp? to significantly upregulate Cathepsin K expression during OC differentiation and activity. In pathologically induced mouse model of osteoporosis, C/ebp? deficiency can protect mice against ovariectomy-induced bone loss, uncovering a central role for C/ebp? in osteolytic diseases. Collectively, our findings have further established C/ebp? as a promising therapeutic target for bone loss by concurrently targeting OC lineage priming, differentiation, and activity. © 2017 American Society for Bone and Mineral Research.

SUBMITTER: Chen W

PROVIDER: S-EPMC6240465 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Monocyte-Specific Knockout of C/ebpα Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebpα in Osteoclast Differentiation and Function.

Chen Wei W Zhu Guochun G Jules Joel J Nguyen Diep D Li Yi-Ping YP

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20180126 4

CCAAT/enhancer-binding protein α (C/ebpα) is critical for osteoclastogenesis by regulating osteoclast (OC) lineage commitment and is also important for OC differentiation and function in vitro. However, the role of C/ebpα in postnatal skeletal development has not been reported owing to lethality in C/ebpα<sup>-/-</sup> mice from hypoglycemia within 8 hours after birth. Herein, we generated conditional knockout mice by deleting the C/ebpα gene in monocyte via LysM-Cre to examine its role in OC di ...[more]

PMID: 29149533

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Project description:Osteoclast lineage commitment and differentiation have been studied extensively, although the mechanism by which transcription factor(s) control osteoclast terminal differentiation, activation, and function remains unclear. CCAAT/enhancer-binding protein α (C/ebpα) has been reported to be a key regulator of osteoclast cell lineage commitment, yet C/ebpα's roles in osteoclast terminal differentiation, activation and function, and bone homeostasis, under physiological or pathological conditions, have not been studied because newborn C/ebpα-null mice die within several hours after birth. Furthermore, the function of C/ebpα in osteoclast terminal differentiation, activation, and function is largely unknown. Herein, we generated and analyzed an osteoclast-specific C/ebpα conditional knockout (CKO) mouse model via Ctsk-Cre mice and found that C/ebpα-deficient mice exhibited a severe osteopetrosis phenotype due to impaired osteoclast terminal differentiation, activation, and function, including mildly reduced osteoclast number, impaired osteoclast polarization, actin formation, and bone resorption, which demonstrated the novel function of C/ebpα in cell function and terminal differentiation. Interestingly, C/ebpα deficiency did not affect bone formation or monocyte/macrophage development. Our results further demonstrated that C/ebpα deficiency suppressed the expression of osteoclast functional genes, e.g. encoding cathepsin K (Ctsk), Atp6i (Tcirg1), and osteoclast regulator genes, e.g. encoding c-fos (Fos), and nuclear factor of activated T-cells 1 (Nfatc1), while having no effect on Pu.1 (Spi1) expression. Promoter activity mapping and ChIP assay defined the critical cis-regulatory element (CCRE) in the promoter region of Nfatc1, and also showed that the CCREs were directly associated with C/ebpα, which enhanced the promoter's activity. The deficiency of C/ebpα in osteoclasts completely blocked ovariectomy-induced bone loss, indicating that C/ebpα is a promising new target for the treatment of osteolytic diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Project description:BackgroundMonocytes/macrophages are likely key cells in immune modulation in dogs with osteosarcoma (OSA). Increased peripheral monocyte counts are negatively correlated with shorter disease-free intervals in dogs with OSA. Understanding the monocyte/macrophage's modulatory role in dogs with OSA can direct further studies in immunotherapy development for OSA.Hypothesis/objectivesThat OSA evades the immune response by down-regulating monocyte chemokine receptor expression and migratory function, and suppresses host immune responses.AnimalsEighteen dogs with OSA that have not received definitive treatment and 14 healthy age-matched controlsMethodsClinical study-expression of peripheral blood monocyte cell surface receptors, monocyte mRNA expression and cytokine secretion, monocyte chemotaxis, and survival were compared between clinical dogs with OSA and healthy control dogs.ResultsCell surface expression of multiple chemokine receptors is significantly down-regulated in peripheral blood monocytes of dogs with OSA. The percentage expression of CCR2 (median 58%, range 2-94%) and CXCR2 expression (median 54%, range 2-92%) was higher in control dogs compared to dogs with OSA (CCR2 median 29%, range 3-45%, P = 0.0006; CXCR2 median 23%, range 0.2-52%, P = 0.0007). Prostaglandin E2 (PGE2 ) (OSA, median 347.36 pg/mL, range 103.4-1268.5; control, 136.23 pg/mL, range 69.93-542.6, P = .04) and tumor necrosis factor-alpha (TNF-α) (P = .02) levels are increased in OSA monocyte culture supernatants compared to controls. Peripheral blood monocytes of dogs with OSA exhibit decreased chemotactic function when compared to control dogs (OSA, median 1.2 directed to random migration, range 0.8-1.25; control, 1.6, range of 0.9-1.8, P = .018).Conclusions and clinical importanceDogs with OSA have decreased monocyte chemokine receptor expression and monocyte chemotaxis, potential mechanisms by which OSA might evade the immune response. Reversal of monocyte dysfunction using immunotherapy could improve survival in dogs with OSA.

Dataset Information

Monocyte-Specific Knockout of C/ebp? Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebp? in Osteoclast Differentiation and Function.

Publications

Monocyte-Specific Knockout of C/ebpα Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebpα in Osteoclast Differentiation and Function.

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