A gain-of-function mutation of the chondrocyte-specific
microRNA, miR-140-5p, encoded by the MIR140 gene, causes
spondyloepiphyseal dysplasia, Nishimura type (SEDN, also known as SED, MIR140 type; MIM, 611894). We reported that a mouse model for SEDN showed a unique growth plate phenotype that is characterized by an expansion of the resting zone of the growth plate and an increase in resting chondrocytes, of which the mechanism of regulation is poorly understood. We found that the miR-140 mutant chondrocytes showed a significant reduction of Hif1a, the master
transcription factor that regulates energy metabolism in response to
hypoxia. Based on this finding, we hypothesized that energy metabolism plays a regulatory role in resting chondrocyte proliferation and growth plate development. In this study, we show that suppression of glycolysis via LDH ablation causes an expansion of the resting zone and skeletal developmental defects. We have also found that reduced glycolysis results in reduced
histone acetylation in the miR-140 mutant as well as LDH-deficient chondrocytes likely due to the reduction in
acetyl-CoA generated from mitochondria-derived
citrate. Reduction in
acetyl-CoA conversion from
citrate by deleting Acly caused an expansion of the resting zone and a similar gross phenotype to LDH-deficient bones without inducing energy deficiency, suggesting that the reduced
acetyl-CoA, but not the
ATP synthesis deficit, is responsible for the increase in resting zone chondrocytes. Comparison of the transcriptome between LDH-deficient and Acly-deficient chondrocytes also showed overlapping changes including upregulation in Fgfr3. We also confirmed that overexpression of an activation mutation of Ffgr3 causes an expansion of resting zone chondrocytes. These data demonstrate the association between reduced glycolysis and an expansion of the resting zone and suggest that it is caused by
acetyl-CoA deficiency, but not energy deficiency, possibly through epigenetic upregulation of FGFR3 signaling.