The role of the sphingosine-1-phosphate signaling pathway in osteocyte mechanotransduction

Zhang, Jianing; Zhao, Yan; Liu, Chao; Han, Elizabeth Shuang; Yu, Xue; Lidington, Darcy; Bolz, Steffen‐Sebastian; You, Lidan

doi:10.1016/j.bone.2015.05.017

Cited by 35 publications

(43 citation statements)

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“…Regarding the bone cells, it was already known that osteoblasts and osteoclasts can produce S1P . Moreover, S1P was identified as a mediator of the mechanosensitive response in murine osteocytic cell lines subjected to fluid flow . Further, regarding tendon cells, an increase in the SPHK1 gene expression was shown after 4 hours of stretching in primary human tenocytes, whereas no stretch‐induced modification of the S1P metabolic pathway was detected in our murine model.…”

Section: Discussionmentioning

confidence: 51%

“…(34,35) Moreover, S1P was identified as a mediator of the mechanosensitive response in murine osteocytic cell lines subjected to fluid flow. (36,37) Further, regarding tendon cells, an increase in the SPHK1 gene expression was shown after 4 hours of stretching in primary human tenocytes, (38) whereas no stretch-induced modification of the S1P metabolic pathway was detected in our murine model. Finally, our results suggested that chondrocytes could be important producers of S1P in the enthesis, which was confirmed by the in situ localization of the SK1 expression in several chondrocytes of sesamoid fibrocartilage (Fig.…”

Section: Discussionmentioning

confidence: 59%

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Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

Jamal

Briolay

Mébarek

et al. 2019

Journal of Bone and Mineral Research

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Spondyloarthritis (SpA) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in SpA pathophysiology. We have previously observed that the levels of sphingosine 1‐phosphate (S1P), a bone anabolic molecule, were particularly high in SpA patients' serum compared to healthy donors. Therefore, we wondered how this deregulation was related to SpA molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF‐α and IL‐17, cytokines implicated in enthesitis, increased Sphk1 mRNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro‐inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR‐induced activation by SpA patients' synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from SpA patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs mRNA, especially S1P1/3, but their contribution to S1P‐impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in SpA enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of SpA. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 59%

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

Jamal

Briolay

Mébarek

et al. 2019

Journal of Bone and Mineral Research

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“…29 IGFBP-2 supported HUVEC proliferation, invasion, and tubule formation in vitro; and knockdown of IGFBP-2 reduced CD31-positive cells in vivo. In fact, cells of the osteogenic lineage are mechanically sensitive 31,[36][37][38][39][40][41][42][43][44][45][46][47][48] and their response includes release of angiogenic factors. High deformational strains and fluid flow shear stress, likely to exist in the fracture regenerate 32 when compliant fixation is used, would act upon resident cells at the fracture site including endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Osteoblast-derived paracrine factors regulate angiogenesis in response to mechanical stimulation

et al. 2016

Self Cite

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Angiogenesis is a process by which new blood vessels emerge from existing vessels through endothelial cell sprouting, migration, proliferation, and tubule formation. Angiogenesis during skeletal growth, homeostasis and repair is a complex and incompletely understood process. As the skeleton adapts to mechanical loading, we hypothesized that mechanical stimulation regulates "osteo-angio" crosstalk in the context of angiogenesis. We showed that conditioned media (CM) from osteoblasts exposed to fluid shear stress enhanced endothelial cell proliferation and migration, but not tubule formation, relative to CM from static cultures. Endothelial cell sprouting was studied using a dual-channel collagen gel-based microfluidic device that mimics vessel geometry. Static CM enhanced endothelial cell sprouting frequency, whereas loaded CM significantly enhanced both frequency and length. Both sprouting frequency and length were significantly enhanced in response to factors released from osteoblasts exposed to fluid shear stress in an adjacent channel. Osteoblasts released angiogenic factors, of which osteopontin, PDGF-AA, IGBP-2, MCP-1, and Pentraxin-3 were upregulated in response to mechanical loading. These data suggest that in vivo mechanical forces regulate angiogenesis in bone by modulating "osteo-angio" crosstalk through release of paracrine factors, which we term "osteokines".

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“…S1P activates the Wnt/β-catenin signaling and thereby induces the OPG expression in osteoblastic cell lines [90]. The CFTR protein has been shown to be involved in the cellular uptake of S1P in a mouse model of heart failure [91,92], and recent data highlight the S1P molecule as a potentially important player in the activity of bone cells by increasing the PGE2 production, reducing the RANKL/OPG ratio expression and ameliorating bone formation [93,94]. It is tempting to speculate that CFTR could be involved in the S1P signalling in bone cells, which would explained some of the aberrant activities observed in CFTR-deficient osteoblasts.…”

Section: Cftr Dysfunction In Bone Cellsmentioning

confidence: 98%

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

Jacquot

Delion²,

Gangloff³

et al. 2015

Osteoporos Int

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Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone-resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD.

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The role of the sphingosine-1-phosphate signaling pathway in osteocyte mechanotransduction

Cited by 35 publications

References 64 publications

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

Osteoblast-derived paracrine factors regulate angiogenesis in response to mechanical stimulation

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

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