Increased joint loading induces subchondral bone loss of the temporomandibular joint via the RANTES-CCRs-Akt2 axis

JCI Insight. 2022 Nov 8;7(21):e158874. doi: 10.1172/jci.insight.158874.

Abstract

Early-stage temporomandibular joint osteoarthritis (TMJOA) is characterized by excessive subchondral bone loss. Emerging evidence suggests that TMJ disc displacement is involved, but the pathogenic mechanism remains unclear. Here, we established a rat model of TMJOA that simulated disc displacement with a capacitance-based force-sensing system to directly measure articular surface pressure in vivo. Micro-CT, histological staining, immunofluorescence staining, IHC staining, and Western blot were used to assess pathological changes and underlying mechanisms of TMJOA in the rat model in vivo as well as in RAW264.7 cells in vitro. We found that disc displacement led to significantly higher pressure on the articular surface, which caused rapid subchondral bone loss via activation of the RANTES-chemokine receptors-Akt2 (RANTES-CCRs-Akt2) axis. Inhibition of RANTES or Akt2 attenuated subchondral bone loss and resulted in improved subchondral bone microstructure. Cytological studies substantiated that RANTES regulated osteoclast formation by binding to its receptor CCRs and activating the Akt2 pathway. The clinical evidence further supported that RANTES was a potential biomarker for predicting subchondral bone loss in early-stage TMJOA. Taken together, this study demonstrates important functions of the RANTES-CCRs-Akt2 axis in the regulation of subchondral bone remodeling and provides further knowledge of how disc displacement causes TMJOA.

Keywords: Bone Biology; Chemokines; Osteoarthritis; Osteoclast/osteoblast biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Diseases, Metabolic* / pathology
  • Bone Remodeling / physiology
  • Cell Line
  • Chemokine CCL5
  • Mice
  • Osteoarthritis* / diagnostic imaging
  • Osteoarthritis* / pathology
  • Osteoclasts / pathology
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Temporomandibular Joint / diagnostic imaging
  • Temporomandibular Joint / pathology

Substances

  • Akt2 protein, rat
  • Chemokine CCL5
  • Proto-Oncogene Proteins c-akt