title: PKCε is a regulator of hypertrophic differentiation of chondrocytes in osteoarthritis.
abstract: Osteoarthritis (OA) is a common and highly debilitating degenerative disease whose complex pathogenesis and the multiplicity of the molecular processes involved, hinder its complete understanding. Protein Kinase C (PKC) novel isozyme PKCε recently proved to be an interesting molecule for further investigations as it can represent an intriguing, new actor in the acquisition of a OA phenotype by the chondrocyte.
  
  
  
  PKCε was modulated in primary chondrocytes from human OA patient knee cartilage samples by means of short hairpin RNA (ShRNA) and the expression of cartilage specific markers observed at mRNA and protein level. The involvement of Histone deacetylases (HDACs) signaling pathway was also investigated through the use of specific inhibitors MS-275 and Inhibitor VIII.
  
  
  
  PKCε loss induces up-regulation of Runt-domain transcription factor (RUNX2), Metalloproteinase 13 (MMP13) and Collagen X (COL10) as well as an enhanced calcium deposition in OA chondrocyte cultures. In parallel, PKCε knock-down also leads to SOX9 and Collagen II (COL2) down-modulation and to a lower deposition of glycosaminoglycans (GAGs) in the extracellular matrix (ECM). This novel regulatory role of PKCε over cartilage hypertrophic phenotype is exerted via an HDAC-mediated pathway, as HDAC2 and HDAC4 expression is modulated by PKCε. HDAC2 and HDAC4, in turn, are at least in part responsible for the modulation of the master transcription factors RUNX2 and SOX9, key regulators of chondrocyte phenotype.
  
  
  
  PKCε prevents the phenotypic progression of the OA chondrocyte, acting on cartilage specific markers through the modulation of the transcription factors SOX9 and RUNX2. The loss of PKCε enhances, in fact, the OA hypertrophic phenotype, with clear implications in the pathophysiology of the disease.
authors.affiliation: Department of Biomedical, Biotechnological &Translational Sciences (S.Bi.Bi.T.), University of Parma, Italy. Electronic address: valeriaqueirolo@libero.it.
authors.forename: V
authors.initials: V
authors.lastname: Queirolo
authors.affiliation: Department of Biomedical, Biotechnological &Translational Sciences (S.Bi.Bi.T.), University of Parma, Italy. Electronic address: daniela.galli@unipr.it.
authors.forename: D
authors.initials: D
authors.lastname: Galli
authors.affiliation: Department of Biomedical, Biotechnological &Translational Sciences (S.Bi.Bi.T.), University of Parma, Italy. Electronic address: elena.masselli82@gmail.com.
authors.forename: E
authors.initials: E
authors.lastname: Masselli
authors.affiliation: Laboratory of Immunorheumatology and Tissue Regeneration/RAMSES, Rizzoli Orthopedic Research Institute, Bologna, Italy. Electronic address: rosamaria.borzi@ior.it.
authors.forename: R M
authors.initials: RM
authors.lastname: Borzì
authors.affiliation: Department of Biomedical, Biotechnological &Translational Sciences (S.Bi.Bi.T.), University of Parma, Italy. Electronic address: silvia.martini1@libero.it.
authors.forename: S
authors.initials: S
authors.lastname: Martini
authors.affiliation: Curriculum of Physical Therapy & Rehabilitation, University of Padova, Italy. Electronic address: fdvitale2015@gmail.com.
authors.forename: F
authors.initials: F
authors.lastname: Vitale
authors.affiliation: Department of Biomedical, Biotechnological &Translational Sciences (S.Bi.Bi.T.), University of Parma, Italy. Electronic address: giuliana.gobbi@unipr.it.
authors.forename: G
authors.initials: G
authors.lastname: Gobbi
authors.affiliation: Department of Biomedical, Biotechnological &Translational Sciences (S.Bi.Bi.T.), University of Parma, Italy. Electronic address: cecilia.carubbi@unipr.it.
authors.forename: C
authors.initials: C
authors.lastname: Carubbi
authors.affiliation: Department of Biomedical, Biotechnological &Translational Sciences (S.Bi.Bi.T.), University of Parma, Italy. Electronic address: prisco.mirandola@unipr.it.
authors.forename: P
authors.initials: P
authors.lastname: Mirandola
mesh_terms: D001549:Benzamides; D002358:Cartilage, Articular; D019902:Chondrocytes; D006801:Humans; D010003:Osteoarthritis; D051744:Protein Kinase C-epsilon; D011725:Pyridines
chemical_list: D001549:Benzamides; D011725:Pyridines; C118739:entinostat; D051744:Protein Kinase C-epsilon
keywords: Cartilage; Chondrocyte differentiation; Osteoarthritis; PKCε