RSK-3 promotes cartilage regeneration via interacting with rpS6 in cartilage stem/progenitor cells

Theranostics. 2020 May 25;10(15):6915-6927. doi: 10.7150/thno.44875. eCollection 2020.

Abstract

Rationale: Cartilage stem/progenitor cells (CSPC) are a promising cellular source to promote endogenous cartilage regeneration in osteoarthritis (OA). Our previous work indicates that ribosomal s6 kinase 3 (RSK-3) is a target of 4-aminobiphenyl, a chemical enhancing CSPC-mediated cartilage repair in OA. However, the primary function and mechanism of RSK-3 in CSPC-mediated cartilage pathobiology remain undefined. Methods: We systematically assessed the association of RSK-3 with OA in three mouse strains with varying susceptibility to OA (MRL/MpJ>CBA>STR/Ort), and also RSK-3-/- mice. Bioinformatic analysis was used to identify the possible mechanism of RSK-3 affecting CSPC, which was further verified in OA mice and CSPC with varying RSK-3 expression induced by chemicals or gene modification. Results: We demonstrated that the level of RSK-3 in cartilage was positively correlated with cartilage repair capacities in three mouse strains (MRL/MpJ>CBA>STR/Ort). Enhanced RSK-3 expression by 4-aminobiphenyl markedly attenuated cartilage injury in OA mice and inhibition or deficiency of RSK-3 expression, on the other hand, significantly aggravated cartilage damage. Transcriptional profiling of CSPC from mice suggested the potential role of RSK-3 in modulating cell proliferation. It was further shown that the in vivo and in vitro manipulation of the RSK-3 expression indeed affected the CSPC proliferation. Mechanistically, ribosomal protein S6 (rpS6) was activated by RSK-3 to accelerate CSPC growth. Conclusion: RSK-3 is identified as a key regulator to enhance cartilage repair, at least partly by regulating the functionality of the cartilage-resident stem/progenitor cells.

Keywords: Cartilage stem/progenitor cell; MRL/MpJ; RSK-3; STR/Ort; osteoarthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobiphenyl Compounds / pharmacology
  • Animals
  • Carcinogens / pharmacology
  • Cartilage / cytology*
  • Cartilage / drug effects
  • Cartilage / metabolism
  • Cells, Cultured
  • Chondrocytes / cytology*
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Inbred MRL lpr
  • Mice, Knockout
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • Osteoarthritis / therapy*
  • Regeneration*
  • Ribosomal Protein S6 / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Stem Cells / metabolism

Substances

  • Aminobiphenyl Compounds
  • Carcinogens
  • Ribosomal Protein S6
  • ribosomal protein S6, mouse
  • 4-biphenylamine
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3