Fig. 6: Treatment with the SERCA2 agonist ISTA improves bone mechano-responsiveness in genetically spontaneous T2D KK-Ay mice.

a The experimental protocol of the ISTA treatment (intravenous infusion of 73 μg/kg body weight per min for 15 min every other day with three times per week from the first day of exogenous cyclic loading), and subsequent application of cyclic compressive loading (1200 cycles/day) on the tibiae in KK-Ay mice for 2 weeks. b–d Representative micro-CT images showing proximal tibial trabecular bone microstructure and cortical bone porosity in KK-Ay mice, and the corresponding statistical results. e Three-point bending testing to analyze whole-bone mechanical properties in KK-Ay mice. f–h Immunohistochemical staining showing the protein expression of sclerostin, RANKL, and OPG in osteocytes in tibial cortical bone matrix of KK-Ay mice. i Representative TRAP staining to label osteoclasts on tibial bone surfaces in KK-Ay mice, and the corresponding statistical result. j Toluidine blue staining to label osteoblasts on tibial trabecular bone surface in KK-Ay mice. k Representative calcein and alizarin red double labeling of tibial trabecular bone surfaces in KK-Ay mice, and the corresponding statistical result. Graphs represent mean ± SD (n = 8 mice per group). *P < 0.05, **P < 0.01, and ***P < 0.001 by two-way ANOVA with Bonferroni’s post test. Specific P values are provided in the Source Data file. Scale bars: f–h, j 20 μm; i 30 μm; k 50 μm.