Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH)

Abstract

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol’s therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.

Curcumin and Resveratrol: Nutraceuticals with so Much Potential for Pseudoachondroplasia and Other ER-Stress Conditions

“…Testing of a coconut oil dispersion of curcumin, CurQ+ [16], in young MT-COMP mice, a model of PSACH, completely restored limb growth [17]. Resveratrol treatment resolved pain and prevented joint degeneration in adult MT-COMP mice [18]. These findings suggest that resveratrol and curcumin may provide a therapeutic benefit for PSACH.…”

“…Prolonged ER stress results in TNFα/TRAIL and CHOP activation that, in turn, elevate mTORC1 signaling, blocking autophagy-thereby preventing the clearance of the ER [11,27]. Orange bar block (⊥) represents inhibition associated with resveratrol and CurQ+, including inflammation, TNFα, oxidative stress, ER stress, PERK, and CHOP [10,12,13,17,18,48].…”

“…Pain in the MT-COMP mice has been established through multiple assays, including alterations of gait [27], voluntary running, and grooming [18]. The parents of PSACH young children describe their children as resting more than their peers, tiring easily, and frequently complaining of leg pain that limits stamina (personal communication).…”

“…Curcumin exerts its anti-inflammatory effects by reducing various cytokines, including those involved in interleukin (IL) activation, tumor necrosis factor-alpha (TNF-α), and the nuclear factor-kappa B pathway [5,58,67] (Figure 2). On the other hand, resveratrol targets IL-1β, TNF-α, and cyclooxygenase-2 to achieve its antiinflammatory activity [18,27,48,59,60,[68][69][70]. The upregulation of SIRT1 by curcumin and resveratrol plays a pivotal role in driving their anti-inflammatory activities [28,63,[71][72][73][74][75] (Figures 1 and 2).…”

“…Despite these positive outcomes, there are significant challenges to nutraceutical therapy. In this review, the PSACH pathology will be discussed along with the relevant stresses that curcumin and resveratrol impact [1,10,[12][13][14]17,18,[26][27][28]. Finally, the hurdles to using natural compounds as therapeutics will be discussed, including one obstacle that is inherent to the compounds: bioavailability.…”