Joint degeneration in a mouse model of pseudoachondroplasia: Er stress, inflammation and block of autophagy

Jacqueline T. Hecht, Alka C. Veerisetty, Mohammad G. Hossain, Debabrata Patra, Frankie Chiu, Francoise Coustry, Karen L. Posey

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3 Scopus citations


Pseudoachondroplasia (PSACH), a short limb skeletal dysplasia associated with premature joint degeneration, is caused by misfolding mutations in cartilage oligomeric matrix protein (COMP). Here, we define mutant-COMP-induced stress mechanisms that occur in articular chondrocytes of MT-COMP mice, a murine model of PSACH. The accumulation of mutant-COMP in the ER occurred early in MT-COMP articular chondrocytes and stimulated inflammation (TNFα) at 4 weeks, and articular chondrocyte death increased at 8 weeks while ER stress through CHOP was elevated by 12 weeks. Importantly, blockage of autophagy (pS6), the major mechanism that clears the ER, sustained cellular stress in MT-COMP articular chondrocytes. Degeneration of MT-COMP articular cartilage was similar to that observed in PSACH and was associated with increased MMPs, a family of degradative enzymes. Moreover, chronic cellular stresses stimulated senescence. Senescence-associated secretory phenotype (SASP) may play a role in generating and propagating a pro-degradative environment in the MT-COMP murine joint. The loss of CHOP or resveratrol treatment from birth preserved joint health in MT-COMP mice. Taken together, these results indicate that ER stress/CHOP signaling and autophagy blockage are central to mutant-COMP joint degeneration, and MT-COMP mice joint health can be preserved by decreasing articular chondrocyte stress. Future joint sparing therapeutics for PSACH may include resveratrol.

Original languageEnglish
Article number9239
JournalInternational journal of molecular sciences
Issue number17
StatePublished - Sep 1 2021


  • Articular cartilage
  • Autophagy
  • Cartilage oligomeric matrix protein
  • Chondrocyte
  • Dwarfism
  • ER stress
  • Joint degeneration
  • Pseudoachondroplasia


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