Background Autotaxin (ATX) is a secreted protein produced by various tissues in the body including the liver, adipose tissue and bone. Autotaxin (ATX) is an enzyme with a phospholipase D activity responsible for cleavage of lysophosphatidyl-choline (LPC) in lysophosphatidic acid (LPA). LPA is a bio phospholipid, which acts as a growth factor, affecting proliferation, differentiation, and migration. It has been shown that the biological effect of LPA could be the direct consequence of local production of Autotaxin (ATX) in a given tissue or cell type (1). Recently, we have shown that LPA controls two steps of osteoclastogenesis: the fusion and bone resorption capacity of osteoclasts (2).
Objectives The aim of this study is to test if ATX produced by osteoclasts could play a direct role in osteoclastogenesis and in bone mass control.
Results First we observed that Enpp2 (ATX gene) was a target gene of RANK-L and as a consequence was up regulated during the course of osteoclastogenesis from bone marrow (BM) wild type (WT) cells. Next we generated Ctsk- Cre+;ATXfl/fl mice and use of these animals as a source of osteoclasts-ATX deficient progenitors. In vitro experiments showed a major impact of ATX on osteoclastogenesis and osteoclast mediated bone resorption. Because LPA is massively present in sera, to explore either LPA or ATX putative effect in culture, the use of delipidated serum was mandatory. Using such conditions, we observed a drastic reduction in the number of mature osteoclasts after 5 days of differentiation from BM-WT progenitors, but osteoclasts number were restored by the use of LPA, recombinant ATX plus LPC, or LPC. These results were confirmed by the use of LPA and ATX specific inhibitors (KI16425 and PF8380). Osteocorning bone resorption assays showed that ATX is required for osteoclasts activity, that decreased of 50% when delipidated sera is used in the assays and that was fully restored by the addition of either LPC or recombinant ATX plus LPC.
Conclusions All together, and more specifically the results obtained in presence of LPC alone suggest that (i) ATX is secreted by osteoclasts and (ii) is functionally involved in osteoclast differentiation and function in vitro. Current studies are conducted on Ctsk-Cre+;ATXfl/fl mice to fully characterize the role of ATX in the bone mass control in physiological and pathological conditions due to ageing (osteoporosis) and inflammation (rheumatoid arthritis).
Nishimura S. et al Diabetes. 2014 Dec;63(12):4154–64)
David M.et al J Biol Chem. 2014 Mar 7;289(10):6551–64
Disclosure of Interest None declared