MMP-13 is one of the critical mediators of the effect of HDAC4 deletion on the skeleton.
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.
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010, USA.
Teruyo
T
Nakatani
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010, USA.
Tiffany
T
Chen
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010, USA. Electronic address: ncp234@nyu.edu.
Nicola C
NC
Partridge
D000818:Animals; D001827:Body Height; D001835:Body Weight; D015519:Bone Density; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000473:pathology; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053509:Matrix Metalloproteinase 13 / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010641:Phenotype; D016019:Survival Analysis; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D055114:X-Ray Microtomography
D000071681:Tartrate-Resistant Acid Phosphatase; D053509:Matrix Metalloproteinase 13; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
Cortical bone; Hdac4; Hdac4(−/−)/Mmp13(−/−) double knockout; Mmp13