CK8 phosphorylation induced by compressive loads underlies the downregulation of CK8 in human disc degeneration by activating protein kinase C

Abstract

Cytokeratin 8 (CK8) is a member of the cytokeratins family with multiple functions on the basis of its unique structural hallmark. The aberrant expression of CK8 and its phosphorylation are pertinent with various diseases. We have previously shown that CK8 exists in normal human nucleus pulposus (NP) cells and decreases as the intervertebral disc degenerates. However, the underlying molecular regulatory machinery of CK8 in intervertebral disc degeneration (IDD) has not been clarified. Here, we collected NP samples from patients with idiopathic scoliosis as control and IDD as degenerate groups. We found that CK8 expression decreased in IDD with an increased phosphorylation in degenerate NP cells. Moreover, NP cells were cultured under different compressive load schemes for diverse time duration. We found that compressive loads resulted in phosphorylation and disassembly of CK8 in a time-dependent and degree-dependent manner in vitro. The activation of protein kinase C was a significant molecular factor contributing to this phenomenon. Taken together, this study is the first to address the molecular mechanisms of CK8 downregulation in NP cells. Importantly, our findings provide clues regarding a molecular link between compressive loads and CK8 alterations, which shed a novel light on the etiology of IDD.

Identification of lumbar disc disease hallmarks: a large cross-sectional study

“…The degeneration sign initiates from cell phenotype conversion from notochord cells to small chondrocyte-like nucleus pulposus cells localized within nests (Chen et al 2013). If we judge lumbar spine discs in terms of more sensitive molecular or RNA expression profiling criteria as we addressed previously (Sun et al 2013; Wan et al 2014; Wang et al 2010, 2011), even early degeneration as phenotype B would be diagnosed as LDD. However, grading 1 to grading 3 would generally be considered as Normal according to MRI grading schemes (Pfirrmann et al 2001; Schneiderman et al 1987).…”

Phosphorylation and Reorganization of Keratin Networks: Implications for Carcinogenesis and Epithelial Mesenchymal Transition

“…Phosphorylation of Ser-13 of K20 is increased after PKC activation but it is not clear whether PKC phosphorylates Ser-13 of K20 ( Zhou et al ., 2006 ). Recently, K8 phosphorylation by PKC is known to a major contributing factor for K8 downregulation in human disc degeneration ( Sun et al ., 2013 ).…”

“…Compressive loads induce K8 phosphorylation in human disc generation by activating protein kinase C ( Sun et al ., 2013 ). Shear stress also evokes reorganization of the keratin network via the phosphorylation of K8 by PKC ζ ( Sivaramakrishnan et al ., 2009 ).…”

Landscape of RNAs in human lumbar disc degeneration

“…Both genetic and environmental factors contribute to IDD, the chief of which are genetics [ 2 , 3 ]. The genetics machinery ranges from single-nucleotide variants [ 4 ] and coding genes [ 5 – 8 ], to newly defined noncoding RNAs (ncRNAs).…”