Netrin‐1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis

Mediero, Aránzazu; Wilder, Tuere; Ramkhelawon, Bhama; Moore, Kathryn J.; Cronstein, Bruce N.

doi:10.1096/fj.201600615r

Cited by 29 publications

(40 citation statements)

References 36 publications

(66 reference statements)

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“…In addition to the regulation of immune cell migration, Netrin‐1 was shown to regulate the inflammatory response of macrophages through suppression of COX‐2–mediated PGE2 production and also promote macrophage reprogramming to induce inflammation resolution . Furthermore, Netrin‐1 binding with its receptor Unc5b takes part in osteoclast biology and thus suggested as a therapeutic target for inflammatory bone destructive diseases . In this study, Netrin‐1 and its receptor Unc5b were detected in all samples.…”

Section: Discussionmentioning

confidence: 56%

“…Maruyama, et al determined high levels of Netrin‐1 in the synovial fluid of rheumatoid arthritis patients and Netrin‐1 treatment attenuated bone erosion. In line with, blockade of Netrin‐1/Unc5b prevented bone destruction and reduced the severity of arthritis . Rosenberger, et al reported that Netrin‐1 was strongly induced by hypoxia and pretreatment with exogenous Netrin‐1 abolished the hypoxia‐dependent increases in plasma cytokine concentrations and PMN numbers into the colon, lungs, and kidneys, thus ameliorate mucosal inflammation.…”

Section: Discussionmentioning

confidence: 67%

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Netrin‐1 and its receptor Unc5b as markers of periodontal disease

Günpınar

Meraci

Dündar

2019

J of Periodontal Research

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Objectives The aim of this present study was to evaluate the levels of Netrin‐1 and Unc5b in periodontal health and disease. Background Netrin‐1, acting via its receptor UNC5b, regulates the inflammatory response and takes apart in bone destructive diseases. Methods Samples of gingival crevicular fluid (GCF), whole saliva, and serum were taken from systemically healthy, nonsmoking 20 periodontitis , 20 gingivitis patients, and 20 periodontally healthy subjects at baseline and 4 weeks after nonsurgical periodontal treatment (NSPT). Whole‐mouth and site‐specific clinical periodontal parameters were recorded. Netrin‐1 and Unc5b levels were measured by enzyme‐linked immunosorbent assay. Data were analyzed by nonparametric tests. Results Total amount of Netrin‐1 in GCF was significantly higher in periodontitis than the others, and the levels were significantly reduced after NSPT. Salivary and serum concentrations of Netrin‐1 were significantly different among the study groups (P = .000), and NSPT significantly increased the concentration levels of both salivary and serum Netrin‐1 (P < .05). Healthy subjects had significantly lower GCF (P = .001) and conversely, higher salivary and serum levels of Unc5b than the other groups (P = .002). The GCF levels of Unc5b were significantly reduced (P < .01), and conversely, serum concentrations were significantly increased after NSPT (P < .05). GCF Netrin‐1 and Unc5b total amounts were positively correlated with clinical parameters (P < .01 and P < .05) whereas salivary Netrin‐1 and Unc5b concentrations were negatively correlated with clinical parameters (P < .01 and P < .05). Conclusions The results of this study indicate that Netrin‐1 and its receptor Unc5b may have essential roles in periodontal inflammation and those can be assumed as useful therapeutic agent to control inflammation and periodontal breakdown.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 67%

Netrin‐1 and its receptor Unc5b as markers of periodontal disease

Günpınar

Meraci

Dündar

2019

J of Periodontal Research

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“…After sacrifice, long bones (n ¼ 10 each treatment) were fixed in 70% ethanol and prepared for high-resolution mCT as previously described. (21) Briefly, analyses were performed in Skyscan 1172 mCT (Bruker, WI, USA) using the following imaging parameters: 60 kV, 167 uA, 9.7 micron pixel size, 2000 Â 1332 matrix, 0.3-degree rotation steps, six averages, movement correction of 10, 0.5-mm Al filter. Images were reconstructed using the Skyscan NRECON software (histogram range 0 to 0.085, beam-hardening correction of 40, Gaussian smoothing (factor 1), ring artifact correction of 8).…”

Section: Micro-x-ray Computed Tomography Analysismentioning

confidence: 99%

Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

Conesa-Buendía

Llamas-Granda

Larrañaga-Vera

et al. 2019

Journal of Bone and Mineral Research

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Osteopenia and fragility fractures have been associated with human immunodeficiency virus (HIV) infection. Tenofovir, a common antiviral in HIV treatment, also leads to increases in bone catabolism markers and decreased BMD in children and young adults. In murine models and human cell lines, tenofovir inhibits adenosine triphosphate release and decreases extracellular adenosine levels. Adenosine and adenosine A2A receptor inhibit osteoclast formation, and increase local adenosine concentration with dipyridamole, an agent that blocks adenosine cellular uptake and stimulates new bone formation as well as bone morphogenic protein 2. We hypothesized that tenofovir regulates bone resorption by diminishing endogenous adenosine levels and questioned whether dipyridamole may be a useful treatment to counteract the deleterous bone effects of tenofovir. Primary murine osteoclasts were induced by M‐CSF/RANKL, and the number of TRAP‐positive‐cells was studied after challenge with tenofovir alone or in combination with dipyridamole. Differentiation markers were studied by RT‐PCR and MAPK/NFkB expression by Western blot. Male C57Bl/6 mice were treated as follows: saline 0.9% (control), tenofovir 75 mg/kg/day, dipyridamole 25 mg/kg/day, combination tenofovir/dipyridamole (n = 10, 4 weeks). Calcein/Alizarin Red‐labeling of newly formed bone was used, and long bones were prepared for micro‐computed tomography (μCT)/histology. Tenofovir produced a dose‐dependent increase in osteoclast differentiation (EC50 = 44.5nM) that was reversed by dipyridamole (IC50 = 0.3 μM). Tenofovir increased cathepsin K and NFATc1 mRNA levels and dipyridamole reversed the effect. Dipyridamole reversed the effect of tenofovir on pERK1/2, pp38, and NFkB nuclear translocation. Mice treated with tenofovir lost nearly 10% of their body weight (p < 0.001). μCT revealed decreased BMD and altered trabecular bone in tenofovir‐treated mice, reversed by dipyridamole. TRAP‐staining showed increased osteoclasts in tenofovir‐treated mice (p < 0.005), an effect reversed by dipyridamole. Similar results were obtained for cathepsin K and CD68. RANKL‐positive cells were increased in tenofovir‐treated mice, whereas osteoprotegerin‐positive cells were decreased; both effects were reversed by dipyridamole. These results suggest that treatment with agents that increase local adenosine concentrations, like dipyridamole, might prevent bone loss following tenofovir treatment. © 2019 American Society for Bone and Mineral Research.

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“…Interestingly, Unc5 family netrin-1 receptors were abundant in BMMs ( Supporting Fig. 2), and numerous studies have confirmed the importance of Unc5b (24)(25)(26)(27) and RANK (39)(40)(41) in OC formation. We thus examined the expression levels of these receptors (Unc5b, RANK, integrin aV, and integrin b3) in OCs from control and Myo10 m/m mice (Fig.…”

Section: Similar Osteoporotic Deficit With Elevated Bone Resorption Amentioning

confidence: 77%

“…In addition, the blockade of netrin-1 or Unc5b by monoclonal antibodies also decreases the number of OCs, preventing bone destruction and reducing the severity of K/BxN serum transfer-induced arthritis. (25) The anti-OCs and bone protective effects by anti-Netrin-1 or anti-Unc5b antibodies are also observable in a murine model of multiple myeloma. (26) Moreover, netrin-1 and Unc5b expression are increased during OC differentiation, and blockade of netrin-1 or Unc5b prevents OC differentiation from both murine and human precursors.…”

Section: Introductionmentioning

confidence: 99%

Lack of Myosin X Enhances Osteoclastogenesis and Increases Cell Surface Unc5b in Osteoclast-Lineage Cells

Wang¹,

Pan

Yu³

et al. 2019

Journal of Bone and Mineral Research

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Normal bone mass is maintained by balanced bone formation and resorption. Myosin X (Myo10), an unconventional “myosin tail homology 4‐band 4.1, ezrin, radixin, moesin” (MyTH4‐FERM) domain containing myosin, is implicated in regulating osteoclast (OC) adhesion, podosome positioning, and differentiation in vitro. However, evidence is lacking for Myo10 in vivo function. Here we show that mice with Myo10 loss of function, Myo10m/m, exhibit osteoporotic deficits, which are likely due to the increased OC genesis and bone resorption because bone formation is unchanged. Similar deficits are detected in OC‐selective Myo10 conditional knockout (cko) mice, indicating a cell autonomous function of Myo10. Further mechanistic studies suggest that Unc‐5 Netrin receptor B (Unc5b) protein levels, in particular its cell surface level, are higher in the mutant OCs, but lower in RAW264.7 cells or HEK293 cells expressing Myo10. Suppressing Unc5b expression in bone marrow macrophages (BMMs) from Myo10m/m mice by infection with lentivirus of Unc5b shRNA markedly impaired RANKL‐induced OC genesis. Netrin‐1, a ligand of Unc5b, increased RANKL‐induced OC formation in BMMs from both wild‐type and Myo10m/m mice. Taken together, these results suggest that Myo10 plays a negative role in OC formation, likely by inhibiting Unc5b cell‐surface targeting, and suppressing Netrin‐1 promoted OC genesis. © 2019 American Society for Bone and Mineral Research.

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Netrin‐1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis

Cited by 29 publications

References 36 publications

Netrin‐1 and its receptor Unc5b as markers of periodontal disease

Netrin‐1 and its receptor Unc5b as markers of periodontal disease

Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

Lack of Myosin X Enhances Osteoclastogenesis and Increases Cell Surface Unc5b in Osteoclast-Lineage Cells

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