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The data in this article is related to the research article entitled “Notch2 signaling promotes osteoclast resorption via activation of PYK2” (Jin et al., 2016 [1]). To block Notch signaling activation, we used several gamma-secretase inhibitors (GSIs) and evaluate the inhibitory potential of GSIs on osteoclastogenesis. We measured the effect of GSIs on osteoclastogenesis and normal spreading of osteoclasts by using the mouse bone marrow-derived macrophages (BMMs) which may contributes to insight of physiological relevant of in vivo. This data article suggests valuable approach to GSIs treatment doses and potential of those in the osteoclast differentiation and spreading. Keywords: Osteoclast, Notch, GSI, Differentiation, Spreading