Hippo-PKCζ-NFκB signaling axis: A druggable modulator of chondrocyte responses to mechanical stress
Xiaomin Cai,
Christopher Warburton,
Olivia F. Perez,
Ying Wang,
Lucy Ho,
Christina Finelli,
Quinn T. Ehlen,
Chenzhou Wu,
Carlos D. Rodriguez,
Lee Kaplan,
Thomas M. Best,
Chun-Yuh Huang,
Zhipeng Meng
Affiliations
Xiaomin Cai
Department of Molecular and Cellular Pharmacology, Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
Christopher Warburton
USOAR Scholar Program, Medical Education, University of Miami Miller School of Medicine, Miami, FL, USA
Olivia F. Perez
USOAR Scholar Program, Medical Education, University of Miami Miller School of Medicine, Miami, FL, USA
Ying Wang
Department of Molecular and Cellular Pharmacology, Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
Lucy Ho
Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA
Christina Finelli
Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA
Quinn T. Ehlen
USOAR Scholar Program, Medical Education, University of Miami Miller School of Medicine, Miami, FL, USA
Chenzhou Wu
Department of Molecular and Cellular Pharmacology, Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
Carlos D. Rodriguez
Department of Molecular and Cellular Pharmacology, Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
Lee Kaplan
Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA; Department of Orthopedics, University of Miami, Miami, FL, USA; UHealth Sports Medicine Institute, University of Miami, Miami, FL, USA
Thomas M. Best
Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA; Department of Orthopedics, University of Miami, Miami, FL, USA; UHealth Sports Medicine Institute, University of Miami, Miami, FL, USA
Chun-Yuh Huang
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; USOAR Scholar Program, Medical Education, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA; UHealth Sports Medicine Institute, University of Miami, Miami, FL, USA; Corresponding author
Zhipeng Meng
Department of Molecular and Cellular Pharmacology, Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; USOAR Scholar Program, Medical Education, University of Miami Miller School of Medicine, Miami, FL, USA; Corresponding author
Summary: Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression of NFκB target genes associated with inflammation and matrix degradation. Mechanistically, mechanical loading activates an atypical PKC, PKCζ, which phosphorylates NFκB p65 at Serine 536, stimulating its transcriptional activation. This mechanosensitive activation of PKCζ and NFκB p65 is impeded in cells with gene deletion or chemical inhibition of Hippo core kinases LATS1/2, signifying an essential role of Hippo signaling in this mechanotransduction. A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies.
