Joint Degeneration in a Mouse Model of Pseudoachondroplasia: ER Stress, Inflammation, and Block of Autophagy.

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

doi:10.3390/ijms22179239

Abstract

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.

Highlights

Cartilage oligomeric matrix protein (COMP) is a large, matricellular protein that mediates a variety of cell–cell and cell–matrix interactions [1,2,3,4,5,6,7]
We have shown that mutant-COMP accumulates in the ER of growth plate chondrocytes of MT-COMP mice, beginning at E15 [40]
NMoP mdiifcfeerceonmcpeasrewdetroe0.11 in the detected prior toc1o6ntwroelsekansdoaf saygneo.vMitiTs -sCcoOreMoPf 1f.8emcoumrpparreodtetoog0l.8y9c,arnescpoencttievneltyw(Taasbllees1s)., Tahnedse findings there was a trendshtoowwtahradt jhoignthdeergsecnoerreastiofonrobccounres/icnaMrtiTl-aCgOeMdPammaicgeebayn2d0 wtoeteaklss,cmourechaeta1r6lier than in weeks. (Table 1). tAhetoCt5a7lBsLc\o6recoonft5ro.7l bwaacksgsriogunnifdicsatnratliny,hwighhereeriitnoc2c0uwrseaefkterMaTy-eCaOr [M64P], mwhiciech is again compared to 2.56coinnstihsteenctowntitrholesar(lwyijtohinat dmegaexnimerautmionscoobrseerovefd12in).PTShAiCs Hsc.ore included the cartilage/bone damage score of 0.9 in 20 week MT-COMP mice compared to 0.11 in the controls and a synovitis score of 1.8 compared to 0.89, respectively (Table 1). These findings show that joint degeneration occurs in MT-COMP mice by 20 weeks, much earlier than in the C57BL\6 control background strain, where it occurs after a year [64], which is again consistent with early joint degeneration observed in PSACH

Summary

Introduction

Cartilage oligomeric matrix protein (COMP) is a large, matricellular protein that mediates a variety of cell–cell and cell–matrix interactions [1,2,3,4,5,6,7]. COMP interacts with many extracellular matrix (ECM) proteins, including, but not limited to, collagens types I, II, IX, XII, XIV, matrilin-3, aggrecan, and fibronectin [8,9,10,11,12] and may provide a hub for interaction(s) of collagens with proteoglycans and other ECM proteins [8,9,11]. PSACH birth parameters are normal, and the first sign of the disorder is decelerating linear growth, starting by the end of the first year, and a waddling gait developing by two years of age [29,32]

Methods

Results

Conclusion