There have been three publications on Netrin-1 at the ACR 2015 Annual Meeting in San Francisco. Netrin-1 plays a role in leukocyte function and inflammation or: “Netrin-1 is a laminin-like matrix protein that acts as a chemorepulsant and which is expressed during and required for osteoclast differentiation. In other settings Netrin1 has been reported to play a pathogenic role during inflammation by preventing macrophage egress from inflamed sites.” I like the word egress; I guess Ira Tabas used it for the first time describing macrophage function. What do the studies tell us?
Aranzazu Mediero and colleagues presented: “Netrin-1 and Its Receptor Unc5b Are Novel Targets for the Treatment of Inflammatory Arthritis.” Conclusion: “Blockade of Netrin-1 and its receptor Unc5b by treatment, in vivo, with murine monoclonal antibodies prevents bone destruction and K/BxN serum transfer-induced arthritis. Netrin-1 may be a novel therapeutic target for inflammatory bone destruction and other forms of osteoclast-mediated bone resorption.” Which means, we could expect from this principle a drug against erosive rheumatoid arthritis and would have to look closely if inflammation per se would be reduced.
The second study was also presented by Aranzazu Mediero: “Stimulation of the Adenosine A2A Receptor (A2AR) Regulates the Expression of Netrin-1 (Ntn1) and Its Receptors (Unc5b, DCC) and Inhibits Wear Particle-Induced Inflammatory Osteolysis in a Model of Joint Prosthesis Loosening.” Conclusion: “Ntn1 expression on macrophages and OC plays a central role in wear particle-induced osteolysis and adenosine A2AR stimulation downregulates Ntn1expression and inhibits bony destruction at sites of wear particle-induced osteolysis. Moreover, Ntn1-unc5b and A2AR stimulation reciprocally diminish signaling by each other. These results suggest that targeting Ntn1 directly or via stimulation of adenosine A2AR may be a novel approach to prevent osteolysis and joint prosthesis loosening.”
Also the third study was presented by Aranzazu Mediero: “Netrin-1 and Its Receptors Unc5b and DCC May be Useful Targets for Preventing Multiple Myeloma Bone Lesions”. Conclusion: “Anti-netrin-1 and -Unc5b treatment decreases osteoclast formation in a murine model of myeloma and decreases myeloma bone lesions. Targeting Netrin-1 or its receptor Unc5b may be a novel therapeutic approach for multiple myeloma.”
The researchers around Aranzazu Mediero presented data on Netrin-1, which showed to influence inflammatory bone destruction and resorption. Netrin-1 might be a target to treat rheumatoid arthritis as well as other diseases.
Mediero A, Wilder T, Cronstein B. Netrin-1 and Its Receptor Unc5b Are Novel Targets for the Treatment of Inflammatory Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/netrin-1-and-its-receptor-unc5b-are-novel-targets-for-the-treatment-of-inflammatory-arthritis/. Accessed December 11, 2015.
Mediero A, Ramkhelawon B, Perez-Aso M, Moore K, Cronstein B. Stimulation of the Adenosine A2A Receptor (A2AR) Regulates the Expression of Netrin-1 (Ntn1) and Its Receptors (Unc5b, DCC) and Inhibits Wear Particle-Induced Inflammatory Osteolysis in a Model of Joint Prosthesis Loosening [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/stimulation-of-the-adenosine-a2a-receptor-a2ar-regulates-the-expression-of-netrin-1-ntn1-and-its-receptors-unc5b-dcc-and-inhibits-wear-particle-induced-inflammatory-osteolysis-in-a-model-o/. Accessed December 11, 2015.
Mediero A, Wilder T, Cronstein B. Netrin-1 and Its Receptors Unc5b and DCC May be Useful Targets for Preventing Multiple Myeloma Bone Lesions [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/netrin-1-and-its-receptors-unc5b-and-dcc-may-be-useful-targets-for-preventing-multiple-myeloma-bone-lesions/. Accessed December 11, 2015.