Compression regulates gene expression of chondrocytes through HDAC4 nuclear relocation via PP2A-dependent HDAC4 dephosphorylation.
Biomechanics plays a critical role in the modulation of chondrocyte function. The mechanisms by which mechanical loading is transduced into intracellular signals that regulate chondrocyte gene expression remain largely unknown. Histone deacetylase 4 (HDAC4) is specifically expressed in chondrocytes. Mice lacking HDAC4 display chondrocyte hypertrophy, ectopic and premature ossification, and die early during the perinatal period. HDAC4 has a remarkable ability to translocate between the cell's cytoplasm and nucleus. It has been established that subcellular relocation of HDAC4 plays a critical role in chondrocyte differentiation and proliferation. However, it remains unclear whether subcellular relocation of HDAC4 in chondrocytes can be induced by mechanical loading. In this study, we first report that compressive loading induces HDAC4 relocation from the cytoplasm to the nucleus of chondrocytes via stimulation of Ser/Thr-phosphoprotein phosphatases 2A (PP2A) activity, which results in dephosphorylation of HDAC4. Dephosphorylated HDAC4 relocates to the nucleus to achieve transcriptional repression of Runx2 and regulates chondrocyte gene expression in response to compression. Our results elucidate the mechanism by which mechanical compression regulates chondrocyte gene expression through HDAC4 relocation from the cell's cytoplasm to the nucleus via PP2A-dependent HDAC4 dephosphorylation.
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan 030001, China.
Chongwei
C
Chen
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan 030001, China.
Xiaochun
X
Wei
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan 030001, China; Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
Shaowei
S
Wang
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan 030001, China.
Qiang
Q
Jiao
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan 030001, China; Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
Yang
Y
Zhang
Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
Guoqing
G
Du
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan 030001, China.
Xiaohu
X
Wang
Foot and Ankle Orthopaedic Surgery Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
Fangyuan
F
Wei
Foot and Ankle Orthopaedic Surgery Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
Jianzhong
J
Zhang
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan 030001, China; Department of Orthopaedics, Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI 02903, USA. Electronic address: lei_wei@brown.edu.
Lei
L
Wei
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D049109:Cell Proliferation / Q000235:genetics; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology*; D020219:Chondrogenesis / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical; D013997:Time Factors
D050659:Core Binding Factor Alpha 1 Subunit; D004791:Enzyme Inhibitors; D012097:Repressor Proteins; C493716:Runx2 protein, mouse; D054648:Protein Phosphatase 2; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
Chondrocytes; Compression; Gene expression; HDAC4; Mechanical loading