Finally, there is a great need for further clarifications of both the physiological and pathological roles of the cloned nSMases. Aside from some of the studies of nSMase2 in bone homeostasis and development, the in vivo functions of both nSMase1 and nSMase3 are not known. Notably, unlike acid SMase knockout mice, which show SM accumulation in various tissues (Horinouchi et al., 1995; Otterbach and Stoffel, 1995), neither nSMase1 nor nSMase2 KO mice appear to demonstrate large abnormalities in SM levels (Stoffel et al., 2005). Thus, complementary and compensatory roles may exist among the different nSMases, the development of conditional KO mouse, as well as double and/or triple SMase KO mouse strains with different combination of SMases may become an essential tool for our future understanding of the physiological and pathological roles of N-SMases.
