Netrin‐4 derived from murine vascular endothelial cells inhibits osteoclast differentiation in vitro and prevents bone loss in vivo

Enoki, Yuichiro; Sato, Tsuyoshi; Tanaka, Shinya; Iwata, Takanori; Usui, Michihiko; Takeda, Satoshi; Kokabu, Shoichiro; Matsumoto, Masahito; Okubo, Masahiko; Nakashima, Keisuke; Yamato, Masayuki; Okano, Teruo; Fukuda, Tsuyoshi; Chida, Dai; Imai, Yuuki; Yasuda, Hisataka; Nishihara, Tatsuji; Akita, Masumi; Oda, Hiromi; Okazaki, Yasushi; Suda, Toshio; Yoda, Tetsuya

doi:10.1016/j.febslet.2014.05.009

Cited by 29 publications

(30 citation statements)

References 36 publications

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“…3, G-I). Other than netrin 1, osteoblasts produce osteoclast inhibitory axon guidance factors such as Sema3A (24), EphB4 (25), and netrin 4 (26). A comparison of these axon guidance factors showed that netrin 1 was the most potent inhibitor of osteoclastogenesis (Fig.…”

Section: Netrin 1 Is Expressed In Osteoblasts Andmentioning

confidence: 99%

Bone-protective Functions of Netrin 1 Protein

Maruyama

Kawasaki

Hamaguchi³

et al. 2016

Journal of Biological Chemistry

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Edited by Amanda FosangNetrin 1 was initially identified as an axon guidance factor, and recent studies indicate that it inhibits chemokine-directed monocyte migration. Despite its importance as a neuroimmune guidance cue, the role of netrin 1 in osteoclasts is largely unknown. Here we detected high netrin 1 levels in the synovial fluid of rheumatoid arthritis patients. Netrin 1 is potently expressed in osteoblasts and synovial fibroblasts, and IL-17 robustly enhances netrin 1 expression in these cells. The binding of netrin 1 to its receptor UNC5b on osteoclasts resulted in activation of SHP1, which inhibited VAV3 phosphorylation and RAC1 activation. This significantly impaired the actin polymerization and fusion, but not the differentiation of osteoclast. Strikingly, netrin 1 treatment prevented bone erosion in an autoimmune arthritis model and age-related bone destruction. Therefore, the netrin 1-UNC5b axis is a novel therapeutic target for bone-destructive diseases.

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Section: Netrin 1 Is Expressed In Osteoblasts Andmentioning

confidence: 99%

Bone-protective Functions of Netrin 1 Protein

Maruyama

Kawasaki

Hamaguchi³

et al. 2016

Journal of Biological Chemistry

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“…Affinity‐purified rabbit polyclonal antibody specific for Cryba4 was raised against the synthetic peptide with the sequence HSGDYKHFREWGSH (Eurofins Genomics K.K., Tokyo, Japan). cDNAs from mouse lens, mouse Achilles tendon and mouse masseter muscle and tendon were prepared as described in a previous paper (Enoki et al., ).…”

Section: Methodsmentioning

confidence: 99%

Possible association of oestrogen and Cryba4 with masticatory muscle tendon‐aponeurosis hyperplasia

et al. 2018

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“…We have previously demonstrated that Ntn4, derived from vascular endothelial cells inhibits osteoclast differentiation (13). We speculate that netrin family may play a vital role for bone metabolism.…”

Section: Discussionmentioning

confidence: 83%

“…To validate changes in gene expression, quantitative real time RT-PCR (qPCR) analysis was performed using Applied Biosystems Prism 7900HT Sequence Detection System according to the manufacturer's instructions (Thermo Scientific, Wilmington, DE, USA) as previously described (13). Total RNA was extracted from cells using ISOGEN (Nippon Gene, Tokyo, Japan).…”

Section: Quantitative Reverse-transcriptase Polymerase Chain Reactionmentioning

confidence: 99%

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Functional Roles of Netrin-1 in Osteoblast Differentiation

Sato

Kokabu

Enoki

et al. 2017

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Bone tissue is constantly being remodeled to maintain its homeostasis by osteoblasts and the resorption by osteoclasts (1). The function of bone tissue is regulated by several factors which other organs produce to communicate with bones. Indeed, the vessels and nerves inside bone are essential for bone development and remodeling (2, 3). Previous studies have demonstrated that neural and vascular regulation factors, such as semaphorins and netrins, orchestrate bone metabolism. We have demonstrated that semaphorin 3A, which is a diffusible axonal chemorepellent that has an important role in axon guidance, regulates bone remodeling indirectly by modulating sensory nerve development and also found that it enhances the elongation of dendrite in osteocytes (4, 5). Semaphorin 3A exerts an osteoprotective effect by both suppressing bone resorption and increasing bone formation (6).Mammalian netrins including the secreted proteins (netrin-1, netrin-3, netrin-4 and netrin-5) and membrane-bound proteins (netrin-G1 and netrin-G2) are involved in the regulation of both axon guidance and angiogenesis (7). The netrin system comprises of seven receptors including neogenin (Neo1), deleted in colorectal carcinoma (DCC), Unc5A, Unc5B, Unc5C, Unc5D, adenosine 2b (A2b), and Down syndrome cell adhesion molecule (DSCAM) (7). Among these netrins, netrin-1 (Ntn1) has involved in cytoskeleton reorganization and in epithelial cell adhesion and migration in lung, mammary gland, and pancreas (8-10). Recent studies showed that Ntn1 plays a crucial role in osteoclast differentiation (11,12). As the function of osteoclasts is regulated by Ntn1, the question whether Ntn1 affects cellular function in osteoblasts has been raised. However, little is known about the role of Ntn1 in osteoblasts. In this study, we explore whether Ntn1 affects the function of osteoblasts. Materials and ΜethodsCell culture, reagents and transfection. The mouse pre-osteoblastic cell line MC3T3-E1 cells which were kindly provided from Dr. Toru Ogasawara (Department of Oral and Maxillofacial Surgery, The University of Tokyo, Japan) were maintained in the medium, 321

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Netrin‐4 derived from murine vascular endothelial cells inhibits osteoclast differentiation in vitro and prevents bone loss in vivo

Cited by 29 publications

References 36 publications

Bone-protective Functions of Netrin 1 Protein

Bone-protective Functions of Netrin 1 Protein

Possible association of oestrogen and Cryba4 with masticatory muscle tendon‐aponeurosis hyperplasia

Functional Roles of Netrin-1 in Osteoblast Differentiation

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