The roles of prostanoids, leukotrienes, and platelet-activating factor in bone metabolism and disease

Hikiji, Hisako; Takato, Tsuyoshi; Shimizu, Takao; Ishii, Satoshi

doi:10.1016/j.plipres.2007.12.003

Cited by 100 publications

(97 citation statements)

References 288 publications

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“…Among phospholipase A 2 (PLA 2 ) enzymes, cPLA 2 ␣ plays a dominant role in arachidonic acid release (18,43). Arachidonic acid is metabolized to eicosanoids including LTB 4 and prostaglandin E 2 (PGE 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…Osteoclasts and osteoblasts participate in bone remodeling under the control of many hormones, cytokines (16,17), and autacoids, including lipid mediators (18). The effects of LTB 4 on bone resorption were investigated using organ cultures of mouse calvariae (19,20).…”

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confidence: 99%

“…The clinically important hard-tissue diseases are inflammatory joint diseases and metabolic bone diseases (18). Inflammatory joint diseases include rheumatoid arthritis characterized by leukocyte infiltration and synovitis accompanied by erosions of cartilage and subchondral bone (21).…”

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confidence: 99%

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A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

Hikiji

Ishii

Yokomizo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Although leukotriene B4 (LTB4) is produced in various inflammatory diseases, its functions in bone metabolism remain unknown. Using mice deficient in the high-affinity LTB4 receptor BLT1, we evaluated the roles of BLT1 in the development of two bone resorption models, namely bone loss induced by ovariectomy and lipopolysaccharide. Through observations of bone mineral contents and bone morphometric parameters, we found that bone resorption in both models was significantly attenuated in BLT1-deficient mice. Furthermore, osteoclasts from BLT1-deficient mice showed reduced calcium resorption activities compared with wild-type osteoclasts. Osteoclasts expressed BLT1, but not the low-affinity LTB4 receptor BLT2, and produced LTB4. LTB4 changed the cell morphology of osteoclasts through the BLT1-Gi protein-Rac1 signaling pathway. Given the causal relationship between osteoclast morphology and osteoclastic activity, these findings suggest that autocrine/paracrine LTB4 increases the osteoclastic activity through the BLT1-Gi protein-Rac1 signaling pathway. Inhibition of BLT1 functions may represent a strategy for preventing bone resorption diseases.bone remodeling ͉ G protein-coupled receptor ͉ knockout mice ͉ lipid mediator ͉ osteoporosis ͉ L eukotriene B 4 (LTB 4 ), a metabolite of arachidonic acid, is a potent lipid mediator with various biological activities toward neutrophils and differentiated T cells, including chemotaxis, degranulation, and production of superoxide anions (1, 2). These actions of LTB 4 are mediated by specific cell surface receptors (BLTs). We previously cloned two distinct BLTs, BLT1 and BLT2 (3,4). BLT1 is a high-affinity receptor that mediates the inhibition of adenylate cyclase and calcium entry by coupling with the Gi-and Gq-classes of G proteins (5). BLT2 transduces comparable intracellular signals but has a lower affinity to LTB 4 (5). Although several hydroxyeicosatetraenoic acids were found to activate BLT2 (6), we recently identified 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT) as a very potent endogenous ligand for BLT2 (7). LTB 4 is produced in inf lammatory diseases such as psoriasis (8), bronchial asthma (9), ulcerative colitis (10), postischemic tissue injuries (11), and rheumatoid arthritis (12-15).Bone remodeling consists of old bone resorption by osteoclasts and new bone deposition by osteoblasts. Osteoclasts and osteoblasts participate in bone remodeling under the control of many hormones, cytokines (16,17), and autacoids, including lipid mediators (18). The effects of LTB 4 on bone resorption were investigated using organ cultures of mouse calvariae (19,20). LTB 4 enhanced calcium efflux from the mouse calvariae, suggesting that LTB 4 stimulates bone resorption (19). LTB 4 increased the formation of resorption pits by osteoclasts in rat bone tissues (20), suggesting that LTB 4 modulates bone resorption by increasing the number and/or activity of osteoclasts. However, few reports have provided definitive biochemical information about the mRNA/protein expression and ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

Hikiji

Ishii

Yokomizo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…It has previously been noted that prostaglandins act as autacoids in osteoblasts (7). Prostaglandins, which have previously been recognized as potent bone-resorptive agents (8), are known to play important roles also in the process of bone formation (8,9).…”

Section: Introductionmentioning

confidence: 99%

Mimosine suppresses the PGF2α-induced synthesis of osteoprotegerin but not interleukin-6 in osteoblasts

Kuroyanagi

Otsuka

Yamamoto

et al. 2016

International Journal of Molecular Medicine

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Abstract. Mimosine, a plant amino acid, is known to act as a normoxic inducer of hypoxia-inducible factor (HIF). Previous research has suggested that HIF plays important roles in angiogenesis-osteogenesis coupling and bone metabolism. We previously reported that prostaglandin F 2α (PGF 2α ) induced osteoprotegerin synthesis through p38 mitogen-activated protein (MAP) kinase, p44/p42 MAP kinase and stressactivated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. We have also demonstrated that PGF 2α induced the synthesis of interleukin-6 (IL-6) via p38 MAP kinase and p44/p42 MAP kinase but not SAPK/JNK in these cells. In the present study, we investigated the effects of mimosine on the PGF 2α -induced synthesis of osteoprotegerin or IL-6 in MC3T3-E1 cells. We found that deferoxamine, another inducer of HIF, as well as mimosine, upregulated the protein levels of HIF-1α. Both mimosine and deferoxamine significantly suppressed the PGF 2α -induced release of osteoprotegerin, and the mRNA expression level, without markedly affecting PGF 2α -induced IL-6 release. Both mimosine and deferoxamine, by themselves, induced the release of vascular endothelial growth factor. The phosphorylation of p38 MAP kinase, p44/p42 MAP kinase or SAPK/JNK induced by PGF 2α was not markedly affected by either mimosine or deferoxamine. Thus, the results of the present study strongly suggest that mimosine, a normoxic inducer of HIF, inhibits the PGF 2α -induced osteoprotegerin synthesis without affecting the IL-6 synthesis in osteoblasts. IntroductionBone metabolism is regulated strictly by two types of functional cells, osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively (1). Bone remodeling is known to be the outcome of the coupling and fine-tuning process of osteoblastic bone formation and osteoclastic bone resorption (1). Numerous humoral factors, including cytokines and prostaglandins, have been demonstrated to participate in bone remodeling (2). Osteoprotegerin, which belongs to the tumor necrosis factor receptor family, along with receptor activator of nuclear factor-κB (RANK), is synthesized by osteoblasts and plays an inhibitory role in osteoclastic differentiation and activation (3). Osteoprotegerin, secreted by osteoblasts, binds to RANK ligand (RANKL) as a decoy receptor, and prevents RANKL from binding to RANK, resulting in the inhibition of bone resorption (3). It has been reported in previous research that RANKL knock-out mice and osteoprotegerin knock-out mice suffered from severe osteopetrosis and osteoporosis, respectively (4,5). Therefore, it has been firmly established that the RANK/RANKL/osteoprotegerin axis is a major regulatory aspect of bone remodeling (6).It has previously been noted that prostaglandins act as autacoids in osteoblasts (7). Prostaglandins, which have previously been recognized as potent bone-resorptive agents (8), are known to play important roles also in the process of bone formation (8,9). Of the prostaglandins,...

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“…Prostaglandins are important autocrine/paracrine modulators in bone metabolism (8), and include prostaglandin E 1 (PGE 1 ), which has been identified as a potent bone-resorptive agent (9). It is currently accepted that osteoblasts are vital in the regulation of bone resorption through activation of receptor activator of NF-κB ligand (RANKL) (10).…”

Section: Introductionmentioning

confidence: 99%

Possible involvement of AMP-activated protein kinase in PGE1-induced synthesis of osteoprotegerin in osteoblasts

Kainuma

Otsuka

Kuroyanagi

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. AMP-activated protein kinase (AMPK) is firmly established as a central regulator of cellular energy homeostasis. We have previously reported that prostaglandin E 1 (PGE 1 ) stimulates the synthesis of osteoprotegerin through p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. The present study investigated the involvement of AMPK in PGE 1 -induced osteoprotegerin synthesis in MC3T3-E1 cells. The levels of osteoprotegerin were measured using an enzyme-linked immunosorbent assay, while the phosphorylation of AMPK, acetyl-CoA carboxylase, p38 MAP kinase and SAPK/JNK were analyzed by western blotting. In addition, the mRNA expression levels of osteoprotegerin were determined by a reverse transcription-quantitative polymerase chain reaction. It was revealed that PGE 1 significantly induced the phosphorylation of the α and β subunits of AMPK in a time-dependent manner (P<0.05). In addition, acetyl-CoA carboxylase, a direct substrate of AMPK, was significantly phosphorylated by PGE 1 (P<0.05). Compound C, an AMPK inhibitor, was revealed to suppress the phosphorylation of acetyl-CoA carboxylase, which significantly reduced the release and mRNA expression levels of PGE 1 -stimulated osteoprotegerin (P<0.05). However, the PGE 1 -induced phosphorylation of p38 MAP kinase and SAPK/JNK were not affected by compound C. The results of the present study indicated that AMPK may positively regulate PGE 1 -stimulated osteoprotegerin synthesis in osteoblasts; thus providing novel insight into the regulatory mechanisms underlying bone metabolism.

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The roles of prostanoids, leukotrienes, and platelet-activating factor in bone metabolism and disease

Cited by 100 publications

References 288 publications

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

Mimosine suppresses the PGF2α-induced synthesis of osteoprotegerin but not interleukin-6 in osteoblasts

Possible involvement of AMP-activated protein kinase in PGE1-induced synthesis of osteoprotegerin in osteoblasts

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The roles of prostanoids, leukotrienes, and platelet-activating factor in bone metabolism and disease

Cited by 100 publications

References 288 publications

A distinctive role of the leukotriene B 4 receptor BLT1 in osteoclastic activity during bone loss

A distinctive role of the leukotriene B 4 receptor BLT1 in osteoclastic activity during bone loss

Mimosine suppresses the PGF2α-induced synthesis of osteoprotegerin but not interleukin-6 in osteoblasts

Possible involvement of AMP-activated protein kinase in PGE1-induced synthesis of osteoprotegerin in osteoblasts

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A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss