CXC receptor knockout mice: Characterization of skeletal features and membranous bone healing in the adult mouse☆

Bischoff, David S.; Sakamoto, Taylor; Ishida, Kazunari; Makhijani, Nalini S.; Gruber, Helen E.; Yamaguchi, Dean T.

doi:10.1016/j.bone.2010.09.026

Cited by 12 publications

(10 citation statements)

References 28 publications

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“…In this study, we also showed that CXCL1 stimulates Erk1/2 phosphorylation in osteoblasts, suggesting a role in osteoblast proliferation and/or differentiation. Our observations are consistent with the studies by Bischoff et al (31), which showed that mCXCR(Ϫ/Ϫ) mice have decreased amounts of trabecular and cortical long bone, suggesting that CXCR2 plays a role in maintaining normal bone homeostasis. Previous studies have shown that the CXCL1/CXCR2 axis plays a major role in neutrophil function, and that CXCR2 is the major mediator of neutrophil migration to sites of inflammation (32).…”

Section: Discussionsupporting

confidence: 83%

Secretome Analysis of an Osteogenic Prostate Tumor Identifies Complex Signaling Networks Mediating Cross-talk of Cancer and Stromal Cells Within the Tumor Microenvironment

Lee

Gajdošik

Josić

et al. 2015

Molecular & Cellular Proteomics

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A distinct feature of human prostate cancer (PCa) is the development of osteoblastic (bone-forming) bone metastases. Metastatic growth in the bone is supported by factors secreted by PCa cells that activate signaling networks in the tumor microenvironment that augment tumor growth. To better understand these signaling networks and identify potential targets for therapy of bone metastases, we characterized the secretome of a patient-derived xenograft, MDA-PCa-118b (PCa-118b), generated from osteoblastic bone lesion. PCa-118b induces osteoblastic tumors when implanted either in mouse femurs or subcutaneously. To study signaling molecules critical to these unique tumor/microenvironment-mediated events, we performed mass spectrometry on conditioned media of isolated PCa-118b tumor cells, and identified 26 secretory proteins, such as TGF-␤2, GDF15, FGF3, FGF19, CXCL1, galectins, and ␤2-microglobulin, which represent both novel and previously published secreted proteins. RT-PCR using human versus mouse-specific primers showed that TGF␤2, GDF15, FGF3, FGF19, and CXCL1 were secreted from PCa-118b cells. A distinct feature of human prostate cancer (PCa) 1 with lethal potential is the development of metastases in bone with a bone-forming phenotype (1). This property of PCa bone metastasis suggests that PCa cells have unique interactions with cells in the bone microenvironment. Cells that are known to be present in the bone microenvironment include osteoblasts, osteoclasts, adipocytes, fibroblasts, and endothelial cells. Communication between PCa cells and each of these cells in the microenvironment is known to promote metastatic growth. This communication involves metastatic PCa cells that secrete factors to affect stromal cells in the bone microenvironment. The tumor-modified stromal cells may further alter the properties of the PCa cells to allow them to progress in the bone environment (1). Determining how secretory proteins from the metastatic PCa cells affect the PCa/stromal communication network will lead to the development of strategies to treat bone metastases.Although men with PCa and bone metastasis most frequently present with osteoblastic bone lesions, the commonly-used PCa cell lines to study metastatic properties, for example, PC3 and C4 -2B, induce osteolytic or mixed osteoblastic/osteolytic lesions, respectively, when the cells are implanted into mouse femurs or tibia (2). In contrast, the PCa118b patient-derived xenograft (PDX), generated from an osteoblastic bone lesion of a patient with PCa and bone metastasis, shows phenotypic characteristics similar to the tumor from which it was derived, including induction of a strong osteoblastic response when implanted into femurs (3). Interestingly, PCa-118b cells are also able to induce ectopic bone formation when implanted subcutaneously (3, 4). TheFrom the

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Section: Discussionsupporting

confidence: 83%

Secretome Analysis of an Osteogenic Prostate Tumor Identifies Complex Signaling Networks Mediating Cross-talk of Cancer and Stromal Cells Within the Tumor Microenvironment

Lee

Gajdošik

Josić

et al. 2015

Molecular & Cellular Proteomics

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“…In addition to CXCL2 dysregulation, our study is the first to show that CXCL1 and the cognate receptor CXCR2 are significantly elevated in response to LPS and amplified in the absence of MKP-1. CXCL1, a heteroisomer of CXCL2 was also shown to be a by-product of endotoxin stimulation with similar function [28, 29]. Physiologically, both CXCL1 and -2 function as chemoattractants during inflammation and potentially as inducers of pre-OC fusion.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, our data indicates that upon priming with M-CSF and RANKL, Dusp1 −/− dOCP have enhanced receptor expression, indicating that these cells have the capacity to respond more robustly than WT counterparts to the elevated cognate chemokines. In a recent study, it was shown that CXCR2 resulted in a significant reduction in both osteoblast and osteoclast formation, resulting in reduced coupled bone turnover in response to wound healing [29]. …”

Section: Discussionmentioning

confidence: 99%

Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2

et al. 2015

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Osteoclast (OC) progenitors (OCP) have been defined in the bone marrow (BM) as CD3−CD45R(B220)−GR1−CD11blo/−CD115+ (dOCP) and more recently in the peripheral blood (PB) as Lym−Ly6G−CD11b+Ly6C+. These progenitors respond to stimuli, including LPS from periopathogenic Aggregatibacter actinomycetemcomitans, activating MAPK signaling, resulting in cytokine/chemokine-mediated osteoclastogenesis. Intracellular negative signaling pathways, including MAPK phosphatase-1 (MKP-1, gene Dusp1) deactivate MAPK pathways (p-p38 and p-JNK) and reduce inflammatory cytokines/chemokines. Objective To delineate the role of MKP-1 in chemokine-mediated OC formation using defined OC progenitor populations. Given its role in innate immune inflammatory signaling, we hypothesize that MKP-1 regulates LPS-induced OC formation from BM OCP through deregulated chemokines. Methods BM and PB from WT and Dusp1−/− female mice (8–12wks) was obtained and sorted into defined progenitor populations. BM sorted dOCP were primed with MCSF and RANKL (48hrs), blocked with vehicle or chemokine blocking antibodies and stimulated with LPS (48–96hrs). TRAP assay and OC activity were measured for OC formation and activity following treatments. Nanostring Array and qPCR were utilized for gene expression analysis. Results Dusp1−/− dOCPs formed more and larger osteoclasts from CD11bhi and dOCP compared to matched WT (P<0.05 each). PB-derived dOCP produced larger and more functional osteoclasts from Dusp1−/− mice compared to WT controls. Nanostring array data revealed significant deregulation in chemokine expression from Dusp1−/− vs. WT cells. qPCR validation of target genes revealed that Dusp1 deficient CD11b+ populations display 1.5–3.5-fold greater expression of CXCL1 and 2–3-fold greater expression of CXCL2 compared to WT in CD11bhi and dOCP (P<0.05 each). Antibody blocking studies using anti-CXCL1 and CXCL2 antibodies blunted osteoclastogenesis in Dusp1−/− cells. Conclusion MKP-1 negatively regulates chemokine-driven OC formation and subsequent bone resorption in response to LPS stimulation. Collectively, these data provide useful insight into mechanisms potentially leading to the development of therapeutic treatment of periodontal disease.

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“…The mechanical properties of femoral bones were tested by three‐point bending tests at the Kureha Special Laboratory Co., Ltd (Tokyo, Japan) using established protocols for mouse bones 27. The span between the two supports of the femur was set at 6 mm; the upper loading device was aligned to the midshaft; and load was applied at a constant displacement rate of 6 mm/min to total failure.…”

Section: Methodsmentioning

confidence: 99%

Adverse effects of hyperlipidemia on bone regeneration and strength

Pirih

et al. 2011

Journal of Bone and Mineral Research

108

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Hyperlipidemia increases the risk for generation of lipid oxidation products, which accumulate in the subendothelial spaces of vasculature and bone. Atherogenic high-fat diets increase serum levels of oxidized lipids, which are known to attenuate osteogenesis in culture and to promote bone loss in mice. In this study, we investigated whether oxidized lipids affect bone regeneration and mechanical strength. Wild type and hyperlipidemic (Ldlr−/−) mice were placed on a high-fat (HF) diet for 13 weeks. Bilateral cranial defects were introduced on each side of the sagittal suture, and 5 weeks post-surgery on the respective diets, the repair/regeneration of cranial bones and mechanical properties of femoral bones were assessed. MicroCT and histological analyses demonstrated that bone regeneration was significantly impaired by the HF diet in WT and Ldlr−/− mice. In femoral bone, cortical bone volume fraction (BV/TV) was significantly reduced while cortical porosity was increased by the HF diet in Ldlr−/− but not in WT mice. Femoral bone strength and stiffness, measured by three-point bending analysis, were significantly reduced by the HF diet in Ldlr−/−, but not in WT mice. Serum analysis showed that the HF diet significantly increased levels of parathyroid hormone, TNF-alpha, calcium and phosphorus, whereas it reduced procollagen type I N-terminal propeptide, a serum marker of bone formation, in Ldlr−/−, but not in WT mice. The serum level of carboxyl-terminal collagen crosslinks, a marker for bone resorption, was also 1.7-fold greater in Ldlr−/− mice. These findings suggest that hyperlipidemia induces secondary hyperparathyroidism and impairs bone regeneration and mechanical strength.

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CXC receptor knockout mice: Characterization of skeletal features and membranous bone healing in the adult mouse☆

Cited by 12 publications

References 28 publications

Secretome Analysis of an Osteogenic Prostate Tumor Identifies Complex Signaling Networks Mediating Cross-talk of Cancer and Stromal Cells Within the Tumor Microenvironment

Secretome Analysis of an Osteogenic Prostate Tumor Identifies Complex Signaling Networks Mediating Cross-talk of Cancer and Stromal Cells Within the Tumor Microenvironment

Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2

Adverse effects of hyperlipidemia on bone regeneration and strength

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