FTY720 enhances osteogenic differentiation of bone marrow mesenchymal stem cells in ovariectomized rats

Huang, Chuang; Ling, Rui; Li, Fei‐Jiang; Li, Er‐Cui; Huang, Qichao; Liu, Bao‐Gang; Ding, Yin; You, Song

doi:10.3892/mmr.2016.5342

Cited by 12 publications

(5 citation statements)

References 32 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The S1Pr1 agonist, FTY720, is a S1P analog approved by the U.S. Food and Drug Administration (FDA) for the treatment of oral diseases and multiple sclerosis. Previous reports showed that locally‐delivered FTY720 could increase bone volume in cranial defects 25,46,47 . In this study, the locally delivered FTY720 loaded in a PEG gel (also FDA approved) promoted bone regeneration by significantly increasing the number of osteoblasts and volume of Type H vessels, which was similar to the beneficial effect of the controlled mechanical loading.…”

Section: Discussionsupporting

confidence: 65%

“…Previous reports showed that locally-delivered FTY720 could increase bone volume in cranial defects. 25,46,47 In this study, the locally delivered FTY720 loaded in a PEG gel (also FDA approved) promoted bone regeneration by significantly increasing the number of osteoblasts and volume of Type H vessels, which was similar to the beneficial effect of the controlled mechanical loading. Additionally, activating S1Pr1 did not directly affect the maturation of osteoprogenitors in vitro, suggesting that S1Pr1 agonistinduced beneficial effect in bone regeneration is mediated mainly by endothelial cells.…”

Section: Discussionsupporting

confidence: 52%

See 1 more Smart Citation

Controlled mechanical loading improves bone regeneration by regulating type H vessels in a S1Pr1 ‐dependent manner

et al. 2022

View full text Add to dashboard Cite

Despite the best treatment, approximately 10% of fractures still face undesirable repair and result in delayed unions or non‐unions. Dynamic mechanical stimulation promotes bone formation, when applied at the correct time frame, with optimal loading magnitude, frequency, and repetition. Controlled mechanical loading significantly increases osteogenic cells during the matrix deposition phase of bone repair. In the bone defect, the blood vessel network guides the initial bone formation activities. A unique blood vessel subtype (Type H) exists in bone, which expresses high levels of CD31 and endomucin, and functions to couple angiogenesis and osteogenesis. However, how this form of controlled mechanical loading regulates the Type H vessels and promotes bone formation is still not clear. Sphingosine 1‐phosphate (S1P) participates in the bone anabolic process and is a key regulator of the blood vessel. Its receptor, sphingosine 1‐phosphate receptor 1 (S1Pr1), is a mechanosensitive protein that regulates vascular integrity. Therefore, we hypothesis that controlled anabolic mechanical loading promotes bone repair by acting on Type H vessels. To study the effect of S1Pr1 on loading induced‐bone repair, we utilized a stabilized tibial defect model, which allows for the application of anabolic mechanical loading. Mechanical loading upregulated S1Pr1 within the entire defect, with up to 80% expressed in blood vessels, as observed by deep tissue imaging. Additionally, S1Pr1 antagonism by W146 inhibited the anabolic effects of mechanical loading. We showed that mechanical loading or activating S1Pr1 could induce YAP nuclear translocation, a key regulator in the cell's mechanical response, in endothelial cells (ECs) in vitro. Inhibition of S1Pr1 in endothelial cells by siRNA reduced loading‐induced YAP nuclear translocation and expressions of angiogenic genes. In vivo, YAP nuclear translocation in Type H vessels was up‐regulated after mechanical loading but was inhibited by antagonizing S1Pr1. S1Pr1 agonist, FTY720, increased bone volume and Type H vessel volume, similar to that of mechanical stimulation. In conclusion, controlled anabolic mechanical loading enhanced bone formation mainly through Type H vessels in a S1Pr1‐dependent manner.

show abstract

Section: Discussionsupporting

confidence: 65%

Section: Discussionsupporting

confidence: 52%

Controlled mechanical loading improves bone regeneration by regulating type H vessels in a S1Pr1 ‐dependent manner

et al. 2022

View full text Add to dashboard Cite

show abstract

“…There are S1P-targeted therapeutic approaches for osteoporosis using S1P lyase inhibitors (e.g., CYM5520 and LX2931) and a structural analog of sphingosine (e.g., FTY720, fingolimod) (Tian et al, 2021). These pharmacological treatments increase S1P at tissue levels, inducing new bone formation, which was confirmed in ovariectomized mice and rat studies (Huang et al, 2016;Weske et al, 2019). Currently, however, it remains unclear whether the expression of S1P receptors in osteocytes has a key regulatory role in response to S1P in the blood, and therefore further studies are required.…”

Section: Sphingolipid Signaling Pathwaymentioning

confidence: 84%

The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States

Choi

Kijas

Lauko

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Bone homeostasis is a dynamic equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts. This process is primarily controlled by the most abundant and mechanosensitive bone cells, osteocytes, that reside individually, within chambers of porous hydroxyapatite bone matrix. Recent studies have unveiled additional functional roles for osteocytes in directly contributing to local matrix regulation as well as systemic roles through endocrine functions by communicating with distant organs such as the kidney. Osteocyte function is governed largely by both biochemical signaling and the mechanical stimuli exerted on bone. Mechanical stimulation is required to maintain bone health whilst aging and reduced level of loading are known to result in bone loss. To date, both in vivo and in vitro approaches have been established to answer important questions such as the effect of mechanical stimuli, the mechanosensors involved, and the mechanosensitive signaling pathways in osteocytes. However, our understanding of osteocyte mechanotransduction has been limited due to the technical challenges of working with these cells since they are individually embedded within the hard hydroxyapatite bone matrix. This review highlights the current knowledge of the osteocyte functional role in maintaining bone health and the key regulatory pathways of these mechanosensitive cells. Finally, we elaborate on the current therapeutic opportunities offered by existing treatments and the potential for targeting osteocyte-directed signaling.

show abstract

“…S1PR/S1P has been shown to be important for osteoclast formation, bone cells that break down bone tissue. A few recent studies have demonstrated that FTY720 binding to S1PR 1 and or S1PR 2 prevents osteoclast formation [258, 259]. By blocking osteoclast formation and reducing bone loss, FTY720 may indirectly have added benefits for advanced cancers that migrate to the bone and where metastasis involves considerable osteolysis [260].…”

Section: S1pr Expression and Malignancymentioning

confidence: 99%

Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget

et al. 2017

View full text Add to dashboard Cite

The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases. SphK is expressed as two isozymes SphK1 and SphK2, transcribed from genes located on different chromosomes and both isozymes catalyze the phosphorylation of sphingosine to S1P. Expression of each SphK isozyme produces alternately spliced isoforms. In recent years the importance of the contribution of SpK1 expression to treatment resistance in cancer has been highlighted and, additionally, differences in treatment outcome appear to also be dependent upon SphK isoform expression. This review focuses on an exciting emerging area of research involving SphKs functions, expression and subcellular localization, highlighting the complexity of targeting SphK in cancer and also comorbid diseases. This review also covers the SphK isoenzymes and isoforms from a historical perspective, from their first discovery in murine species and then in humans, their role(s) in normal cellular function and in disease processes, to advancement of SphK as an oncotarget.

show abstract

FTY720 enhances osteogenic differentiation of bone marrow mesenchymal stem cells in ovariectomized rats

Cited by 12 publications

References 32 publications

Controlled mechanical loading improves bone regeneration by regulating type H vessels in a S1Pr1 ‐dependent manner

Controlled mechanical loading improves bone regeneration by regulating type H vessels in a S1Pr1 ‐dependent manner

The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States

Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget

Contact Info

Product

Resources

About