title: Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes.
abstract: Histone deacetylase 4 (HDAC4) is a critical negative regulator for chondrocyte hypertrophy by binding to and inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. It is unclear how HDAC4 expression and stability are regulated during growth plate development. We report here that inhibition of mitogen-activated protein kinase (MAPK) p38 by dominant negative p38 or p38 inhibitor prevents HDAC4 degradation. Mutation of a potential caspase-2 and 3 cleavage site Asp289 stabilizes HDAC4 in chondrocytes. In contrast, constitutively active MAPK kinase 6 (constitutive activator of p38) transgenic mice exhibit decreased HDAC4 content in vivo. We also observed that p38 stimulates caspase-3 activity in chondrocytes. Inhibition of p38 or caspases reduced HDAC4 degradation. HDAC4 inhibited Runx2 promoter activity in a dose-dependent manner and caspase inhibitors further enhanced this inhibition by preventing HDAC4 degradation. Overall, these results demonstrate that p38 promotes HDAC4 degradation by increasing caspase-mediated cleavage, which releases Runx2 from a repressive influence of HDAC4 and promotes the chondrocyte hypertrophy and bone formation.
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hosptal, Coro West, Suite 402H, 1 Hoppin Street, Providence RI 02903.
authors.forename: Jingming
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hosptal, Coro West, Suite 402H, 1 Hoppin Street, Providence RI 02903.|Department of Orthopaedics, the Second Hospital of Shanxi Medical University; Shanxi Key Lab of Bone and Soft Tissue Injury Repair. Taiyuan, China.
authors.forename: Pengcui
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hosptal, Coro West, Suite 402H, 1 Hoppin Street, Providence RI 02903.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, the Second Hospital of Shanxi Medical University; Shanxi Key Lab of Bone and Soft Tissue Injury Repair. Taiyuan, China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Surgery, Boston University, Roger Williams Medical Center, Providence, Rhode Island 02908.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Dermatology Biology, Boston University, Roger Williams Medical Center, Providence, Rhode Island 02908.
authors.forename: Zhengke
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hosptal, Coro West, Suite 402H, 1 Hoppin Street, Providence RI 02903.|Department of Orthopaedics, the Second Hospital of Shanxi Medical University; Shanxi Key Lab of Bone and Soft Tissue Injury Repair. Taiyuan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002645:Chickens; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D006132:Growth Plate / Q000187:drug effects / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D061945:Caspase Inhibitors; D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482567:Map2k6 protein, mouse; D020169:Caspases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: Caspase; Degradation; HDAC4; Inhibition; p38