Fig. 6. Pharmacological PHGDH inhibition prevents osteoporotic bone loss in mice.
a–c, 3D micro-CT models (a) of the tibial metaphysis (top) and diaphysis (bottom) with quantification of trabecular bone volume (BV/TV; b) and cortical thickness (Ct.Th; c) in sham-operated or ovariectomized (OVX) mice, treated with either vehicle or NCT-503 (n = 6; two-way ANOVA). d,e, TRAP staining of the tibial metaphysis (d) with quantification (e) of osteoclast surface per bone surface (Oc.S/B.S) in sham-operated or OVX mice, treated with either vehicle or NCT-503 (n = 6; two-way ANOVA). Scale bar, 50 µm. f, Serum CTx-I levels in sham-operated or OVX mice, treated with either vehicle or NCT-503 (n = 6; two-way ANOVA). g, Schematic overview of research findings. A transient, RANKL-induced activation of the SSP is required to generate αKG during early osteoclastogenesis, which is subsequently used by histone demethylases to remove the repressive histone mark H3K27Me3 at the Nfatc1 gene locus, thereby inducing NFATc1 expression and consequent osteoclast maturation. Created with BioRender.com. Data are means ± s.d.