Fingolimod suppresses bone resorption in female patients with multiple sclerosis

Miyazaki, Yusei; Niino, Masaaki; Kanazawa, Ippei; Suzuki, Masako; Mizuno, Masanori; Hisahara, Shin; Fukazawa, Toshiyuki; Takahashi, Eri; Amino, Itaru; Ochi, Ryutaro; Nakamura, Masakazu; Akimoto, Sachiko; Minami, Naoya; Fujiki, Naoto; Doi, Shizuki; Shimohama, Shun; Terayama, Yasuo; Kikuchi, Seiji

doi:10.1016/j.jneuroim.2016.06.007

Cited by 8 publications

(5 citation statements)

References 31 publications

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“… 30 Likewise, the bone-protective effect of fingolimod, a selective agonist of S1PR1/3 but not S1PR2 that is used to treat multiple sclerosis, may be attributed to reducing the number of mature osteoclasts on the bone surface by promoting the S1PR1-driven recirculation of OCPs. 29 , 68 The fact that the association of S1P levels with OFs was partly independent of BMD supports the notion that the net impact of circulating S1P in humans may be exerted through impaired cellular bone remodeling rather than a reduction in bone mass. 40 , 57 – 59 These considerations warrant further mechanistic studies that take into account the complex regulation of S1P receptor signaling, which depends on differential S1P gradients.…”

Section: S1p As a Biomarker Of Osteoporosismentioning

confidence: 62%

“…Because, in addition to specific S1PR agonists and antagonists, fingolimod also exerted beneficial effects in the treatment of osteoporosis, the enzymes involved in S1P synthesis and degradation have received considerable attention. 68 Both the activation of SPHK and inhibition of S1P lyase increase S1P levels. In a model of glucocorticoid-associated osteoporosis in vitro, Ji et al showed that the activation of SPHK1 in murine OBs using K6PC-5 increased S1P production and that the subsequent enhanced phosphorylation of AKT protected against glucocorticoid-induced cell death.…”

Section: S1p and S1prs As Potential Targets For The Treatment Of Oste...mentioning

confidence: 99%

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The role of sphingosine-1-phosphate in bone remodeling and osteoporosis

et al. 2022

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Osteoporosis is a systemic bone disease that affects more than 200 million people worldwide and is caused by the disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation. Sphingosine-1-phosphate (S1P) is a natural, bioactive sphingolipid that has been shown to play a major role in cardiovascular and immunological pathologies by regulating biological and cellular processes, including migration, differentiation, proliferation and survival. Recent studies also suggest a central role for S1P in bone diseases, including osteoporosis; however, the effects of S1P, particularly in bone metabolism, remain to be further elucidated. In this review, we summarize the available literature on the role of S1P in bone metabolism with a focus on osteoporosis. On the cellular level, S1P acts as an osteoclast-osteoblast coupling factor to promote osteoblast proliferation and bone formation. Moreover, the recruitment of osteoclast precursors to resorption sites is regulated by the interplay of S1P gradients and S1P receptor expression. From a clinical perspective, increasing evidence suggests that systemically elevated S1P blood levels may serve as an independent risk factor for osteoporosis-related fractures. Taken together, S1P signaling is a potential therapeutic target and may serve as a novel biomarker in patients with systemic bone disease.

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Section: S1p As a Biomarker Of Osteoporosismentioning

confidence: 62%

Section: S1p and S1prs As Potential Targets For The Treatment Of Oste...mentioning

confidence: 99%

The role of sphingosine-1-phosphate in bone remodeling and osteoporosis

et al. 2022

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“…S1P also affects osteoclasts directly, acting to promote osteoclast precursor migration to bone surfaces. When administered in vivo, S1PR agonists limit osteoclast mediated bone resorption induced by ovariectomy in mice and bone resorption associated with multiple sclerosis in humans (39)(40)(41)(42). Our data show that Hdac3 deficiency limits S1P production and suggest that bone coupling is diminished.…”

Section: Discussionmentioning

confidence: 73%

Hdac3 regulates bone modeling by suppressing osteoclast responsiveness to RANKL

Molstad

Mattson

Begun

et al. 2020

Journal of Biological Chemistry

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Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. While Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known Hdac3 activities in bone resorbing osteoclasts. In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NFκB transcriptional complex to decrease DNA binding and transcriptional activity. Hdac3 deficient osteoclasts demonstrate increased K310 NFκB acetylation and NFκB transcriptional activity. Hdac3 deficient osteoclast lineage cells were hyper-responsive to RANKL and showed elevated ex vivo osteoclast number and size and enhanced bone resorption in pit formation assays. Osteoclast-directed Hdac3 deficiency decreased cortical and trabecular bone mass parameters, suggesting that Hdac3 regulates coupling of bone resorption and bone formation. We surveyed a panel of osteoclast-derived coupling factors and found that Hdac3 suppression diminished S1P production. Osteoclast-derived S1P acts in paracrine to promote bone mineralization. Mineralization of wild type bone marrow stromal cells cultured with conditioned medium from Hdac3 deficient osteoclasts was markedly reduced. Expression of Alkaline phosphatase, Type Collagen 1a1 and Osteocalcin was also suppressed, but no change in Runx2 expression was observed. Our results demonstrate that Hdac3 controls bone modeling by suppressing osteoclast lineage cell responsiveness to RANKL and coupling to bone formation.

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“…Fingolimod (FTY720) acts as an agonist of the S1P receptor (S1PR). It could induce internalization and subsequent degradation of the receptor and consequently render lymphocytes to physiological S1P stimulation upon binding to the S1PR expressed on lymphocytes 85 . In addition to its immunology modulatory effects in MS, fingolimod may have a beneficial effect on bone mass loss in female MS patients 57 .…”

Section: The Clinical Development Of Drugs Targeting S1p Receptors Inmentioning

confidence: 99%

Sphingosine‐1‐phosphate (S1P) receptors: Promising drug targets for treating bone‐related diseases

Zhang

Dong

et al. 2020

J Cellular Molecular Medi

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Bone is regarded as a highly dynamic tissue that constantly undergoes cycles of bone resorption and bone formation. The whole cycle is divided into three phases: (a) the interaction of osteoclast precursors (OCPs) and osteoblasts (OBs) on the bone surface, including OCP recruitment, RANKL-RANK binding and adhesion to the bone surface; (b) the differentiation of osteoblast precursors (OBPs) is facilitated by various cytokines from mature osteoclasts; and (c) the apoptosis of osteoclasts (OCs), as well as mineralization of the bone matrix. 1 During these OCPs and OBPs migrate to the bone surface, and various coupling factors, such as receptor activator of nuclear factor-κ B ligand (RANKL), have a dramatic influence on the bone regeneration cycle. Currently, S1P has been recognized to participate in this remodelling cycle, suggesting its significance in bone pathology.Sphingosine-1-phosphate (S1P) is a natural bioactive lipid molecule and a common first or second messenger in the cardiovascular and immune systems. 2,3 At present, research on the role of S1P in the Abstract Sphingosine-1-phosphate (S1P) is a natural bioactive lipid molecule and a common first or second messenger in the cardiovascular and immune systems. By binding with its receptors, S1P can serve as mediator of signalling during cell migration, differentiation, proliferation and apoptosis. Although the predominant role of S1P in bone regeneration has been noted in many studies, this role is not as well-known as its roles in the cardiovascular and immune systems. In this review, we summarize previous research on the role of S1P receptors (S1PRs) in osteoblasts and osteoclasts. In addition, S1P is regarded as a bridge between bone resorption and formation, which brings hope to patients with bone-related diseases. Finally, we discuss S1P and its receptors as therapeutic targets for treating osteoporosis, inflammatory osteolysis and bone metastasis based on the biological effects of S1P in osteoclastic/osteoblastic cells, immune cells and tumour cells. K E Y W O R D Scancer-related bone metastasis, inflammatory osteolysis, osteoporosis, S1P receptors

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Fingolimod suppresses bone resorption in female patients with multiple sclerosis

Cited by 8 publications

References 31 publications

The role of sphingosine-1-phosphate in bone remodeling and osteoporosis

The role of sphingosine-1-phosphate in bone remodeling and osteoporosis

Hdac3 regulates bone modeling by suppressing osteoclast responsiveness to RANKL

Sphingosine‐1‐phosphate (S1P) receptors: Promising drug targets for treating bone‐related diseases

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