MMP-13 is one of the critical mediators of the effect of HDAC4 deletion on the skeleton


Teruyo Nakatani, Tiffany Chen, Nicola C. Partridge


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.