CXCL12/CXCR4 Signal Axis Plays an Important Role in Mediating Bone Morphogenetic Protein 9-induced Osteogenic Differentiation of Mesenchymal Stem Cells

Liu, Chen; Weng, Yaguang; Yuan, Taixian; Zhang, Hong; Bai, Hao; Li, Baolin; Yang, Dandan; Zhang, Ruyi; He, Fang; Yan, Shujuan; Zhan, Xi; Shi, Qiong

doi:10.7150/ijms.6657

Cited by 35 publications

(36 citation statements)

References 42 publications

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“…The CXCL12/CXCR4 axis is cardinal in MSC homing and bone synthesis and Cxcr4 deletion perturbs osteoblastogenesis and bone development. [37][38][39] Therefore, our data most probably suggest that apoA-1 deficiency reduces the function of CXCL12/CXCR4 signaling axis with possible feedback compensation, firing the shift from osteoblast to adipocyte production. The chemokine CXCL12 is established to be regulated, in other marrow contexts, by ANXA2.…”

Section: Discussionmentioning

confidence: 84%

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Blair

Kalyvioti

Papachristou

et al. 2016

Laboratory Investigation

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Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH). In the present study we aimed at further expanding the current knowledge as regards the fascinating bone-HDL connection studying bone turnover in apoA-1-deficient mice. Interestingly, we found that bone mass was greatly reduced in the apoA-1-deficient mice compared with their wild-type counterparts. More specifically, static and dynamic histomorphometry showed that the reduced bone mass in apoA-1 − / − mice reflect decreased bone formation. Biochemical composition and biomechanical properties of ApoA-1 − / − femora were significantly impaired. Mesenchymal stem cell (MSC) differentiation from the apoA-1 − / − mice showed reduced osteoblasts, and increased adipocytes, relative to wild type, in identical differentiation conditions. This suggests a shift in MSC subtypes toward adipocyte precursors, a result that is in line with our finding of increased bone marrow adiposity in apoA-1 − / − mouse femora. Notably, osteoclast differentiation in vitro and osteoclast surface in vivo were unaffected in the knock-out mice. In whole bone marrow, PPARγ was greatly increased, consistent with increased adipocytes and committed precursors. Further, in the apoA-1 − / − mice marrow, CXCL12 and ANXA2 levels were significantly decreased, whereas CXCR4 were increased, consistent with reduced signaling in a pathway that supports MSC homing and osteoblast generation. In keeping, in the apoA-1 − / − animals the osteoblast-related factors Runx2, osterix, and Col1a1 were also decreased. The apoA-1 − / − phenotype also included augmented CEPBa levels, suggesting complex changes in growth and differentiation that deserve further investigation. We conclude that the apoA-1 deficiency generates changes in the bone cell precursor population that increase adipoblast, and decrease osteoblast production resulting in reduced bone mass and impaired bone quality in mice.Laboratory Investigation (2016) 96, 763-772; doi:10.1038/labinvest.2016 published online 18 April 2016 Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone, resulting in bone fragility and fracture susceptibility. 1,2 It is a major public health problem worldwide; indeed, in the United States, more than 44 million people have osteoporosis or low bone mass. 3 The pathogenesis of osteoporosis is multifactorial. Age, sex, body size, metabolic factors, and genetic susceptibility are contributory factors. Interestingly, several studies have shown that there are strong links between bone, fat metabolism, and systemic energy metabolism, and that perturbations in lipid regulatory pathways may trigger both local and systemic phenomena that ultimately affect osteoblast and/or osteoclast function, resulting...

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Section: Discussionmentioning

confidence: 84%

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Blair

Kalyvioti

Papachristou

et al. 2016

Laboratory Investigation

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“…However, Liu et al . reported a reduction of SDF1 mRNA in C3H10T1/2 cells following delivery of BMP‐9 by an adenoviral vector. Our results provide support for an increase in the expression of SDF‐1 following treatment with BMP‐9.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the phosphoinositide 3‐kinase/Akt signaling pathway in bone morphogenetic protein 9‐stimulated osteogenic differentiation and stromal cell‐derived factor 1 production in human periodontal ligament fibroblasts

Furue

Sena

Sakoda

et al. 2017

European J Oral Sciences

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Recent studies have shown that bone morphogenetic protein 9 (BMP-9) can induce osteogenic differentiation in human periodontal stem cells and human periodontal ligament fibroblasts (PDLFs). Bone morphogenetic protein 9 may be used in periodontal tissue regeneration because of its potent osteoinductive ability. Human periodontal ligament cells also have been demonstrated to produce stromal cell-derived factor 1 (SDF-1), which is important for stem-cell homing and recruitment to injured sites. In the present study, we examined the involvement of the phosphoinositide 3-kinase (PI3K)/Akt signaling axis in osteogenic differentiation and SDF-1 production in human PDLFs stimulated with BMP-9 in osteogenic medium supplemented with dexamethasone and ascorbic acid. Pretreatment of the cells with LY294002, a PI3K-specific inhibitor, suppressed not only BMP-9-enhanced alkaline phosphatase activity but also expression of a BMP-response gene (inhibitor of DNA binding 1) and osteogenic marker genes (runt-related transcription factor 2, osterix, bone sialoprotein, and osteopontin). In addition, BMP-9 up-regulated SDF-1 production, and the production of SDF-1 was suppressed by LY294002. The protein SDF-1-alpha was identified as a major isoform of SDF-1 that was regulated by BMP-9. Our data suggest involvement of the PI3K/Akt pathway in BMP-9-stimulated osteogenic differentiation and SDF-1 production in PDLFs cultured in osteogenic medium.

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“…Thus, effects on Cxcl12 are likely intrinsic to the biology of sclerostin inhibition and canonical Wnt signaling in bone. Wnt signaling‐mediated reduction in Cxcl12 and its receptor Cxcr4 promotes osteogenic differentiation of mesenchymal stem cells . Upstream promoter analyses of the other four downregulated B‐cell genes revealed the presence of WREs in three of these genes, suggesting possible regulation by the canonical Wnt pathway.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Laser Capture Microdissected Subpopulations of the Osteoblast Lineage Provides Insight Into the Early Response to Sclerostin Antibody in Rats

Nioi

Taylor

et al. 2015

Journal of Bone and Mineral Research

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Sclerostin antibody (Scl-Ab) increases bone formation through a process dependent on the activation of canonical Wnt signaling, although the specific signaling in the osteoblast lineage in vivo is largely unknown. To gain insight into the signaling pathways acutely modulated by Scl-Ab, the transcriptional response of subpopulations of the osteoblast lineage was assessed by TaqMan and microarray analyses of mRNA isolated from laser capture microdissection (LCM)-enriched samples from the vertebrae of ovariectomized rats during the first week after Scl-Ab administration. Briefly, 6-month-old Sprague-Dawley rats were ovariectomized and, after 2 months, received a single dose of vehicle (VEH) or 100 mg/kg Scl-Ab (n ¼ 20/group). Lumbar vertebrae were collected at 6, 24, 72, and 168 hours postdose and cryosectioned for LCM. Osteocytes were captured from bone matrix, and osteoblasts and lining cells were captured from bone surfaces based on fluorochrome labeling. mRNA was isolated, amplified, and profiled by TaqMan and microarray. Expression analysis revealed that Scl-Ab caused strikingly similar transcriptional profiles across all three cell types. Only 13 known canonical Wnt target genes, the majority with known functions in bone, showed a significant change in expression by microarray in response to Scl-Ab, with Wisp1 and Twist1 being the most responsive. Coincident with increased expression of Wnt target genes was the upregulation of numerous extracellular matrix (ECM) genes. The acute and progressive upregulation of ECM genes in lining cells supports their activation into matrix-producing osteoblasts, consistent with modelingbased bone formation. A similar transcriptional profile in osteocytes may indicate that Scl-Ab stimulates perilacunar/pericanalicular matrix deposition. Pathway analyses indicated that Scl-Ab regulated a limited number of genes related to cell cycle arrest and B-cell development. These data describe the acute downstream signaling in response to Scl-Ab in vivo and demonstrate selected canonical Wnt target gene activation associated with increased bone formation in all mature osteoblast subpopulations.

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CXCL12/CXCR4 Signal Axis Plays an Important Role in Mediating Bone Morphogenetic Protein 9-induced Osteogenic Differentiation of Mesenchymal Stem Cells

Cited by 35 publications

References 42 publications

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Involvement of the phosphoinositide 3‐kinase/Akt signaling pathway in bone morphogenetic protein 9‐stimulated osteogenic differentiation and stromal cell‐derived factor 1 production in human periodontal ligament fibroblasts

Transcriptional Profiling of Laser Capture Microdissected Subpopulations of the Osteoblast Lineage Provides Insight Into the Early Response to Sclerostin Antibody in Rats

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