Histone deacetylase 4 (Hdac4) regulates chondrocyte hypertrophy. Hdac4−/− mice are runted in size and do not survive to weaning. This phenotype is primarily due to the acceleration of onset of chondrocyte hypertrophy and, as a consequence, inappropriate endochondral mineralization. Previously, we reported that Hdac4 is a repressor of matrix metalloproteinase-13 (Mmp13) transcription, and the absence of Hdac4 leads to increased expression of MMP-13 both in vitro (osteoblastic cells) and in vivo (hypertrophic chondrocytes and trabecular osteoblasts). MMP-13 is thought to be involved in endochondral ossification and bone remodeling. To identify whether the phenotype of Hdac4−/− mice is due to up-regulation of MMP-13, we generated Hdac4/Mmp13 double knockout mice and determined the ability of deletion of MMP-13 to rescue the Hdac4−/− mouse phenotype. Mmp13−/− mice have normal body size. Hdac4−/−/Mmp13−/− double knockout mice are significantly heavier and larger than Hdac4−/− mice, they survive longer, and they recover the thickness of their growth plate zones. In Hdac4−/−/Mmp13−/− double knockout mice, alkaline phosphatase (ALP) expression and TRAP-positive osteoclasts were restored (together with an increase in Mmp9 expression) but osteocalcin (OCN) was not. Micro-CT analysis of the tibiae revealed that Hdac4−/− mice have significantly decreased cortical bone area compared with the wild type mice. In addition, the bone architectural parameter, bone porosity, was significantly decreased in Hdac4−/− mice. Hdac4−/−/Mmp13−/− double knockout mice recover these cortical parameters. Likewise, Hdac4−/− mice exhibit significantly increased Tb.Th and bone mineral density (BMD) while the Hdac4−/−/Mmp13−/− mice significantly recovered these parameters toward normal for this age. Taken together, our findings indicate that the phenotype seen in the Hdac4−/− mice is partially derived from elevation in MMP-13 and may be due to a bone remodeling disorder caused by overexpression of this enzyme.
- Cortical bone
- Hdac4/Mmp13 double knockout
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism