Stress‐Induced Activation of Apoptosis Signal‐Regulating Kinase 1 Promotes Osteoarthritis

Abstract

Apoptosis signal-regulated kinase 1 (ASK1) has been shown to affect a wide range of cellular processes including stress-related responses, cytokine and growth factor signaling, cell cycle and cell death. Recently, we reported that lack of ASK1 slowed chondrocyte hypertrophy, terminal differentiation and apoptosis resulting in an increase in trabecular bone formation. Herein, we investigated the role of ASK1 in the pathogenesis of osteoarthritis (OA). Immunohistochemistry performed on articular cartilage samples from patients with OA showed ASK1 expression increased with OA severity. In vitro analysis of chondrocyte hypertrophy, maturation and ASK1 signaling in embryonic fibroblasts from ASK1 knockout (KO) and wild type (WT) mice was examined. Western analysis demonstrated an increase in ASK1 signaling commensurate with chondrogenic maturation during differentiation or in response to stress by the cytokines, tumor necrosis factor alpha or interleukin 1 beta in WT, but not in ASK1 KO embryonic fibroblasts. Surgically induced moderate or severe OA or OA due to natural aging in WT and ASK1 KO mice was assessed by microCT of subchondral bone, immunohistochemistry, histology, and OARSI scoring. Immunohistochemistry, microCT and OARSI scoring all indicated that the lack of ASK1 protected against OA joint degeneration, both in surgically induced OA and in aging mice. We propose that the ASK1 MAP kinase signaling cascade is an important regulator of chondrocyte terminal differentiation and inhibitors of this pathway could be useful for slowing chondrocyte maturation and cell death observed with OA progression.

ASK1 inhibition: a therapeutic strategy with multi-system benefits

“…In vivo, chondrocyte hypertrophy is significantly reduced in untreated two-year-old Ask1 −/− mice, when compared to age-matched Ask1 +/+ mice [93]. As a result, Ask1 −/− mice experience significantly less age-related cartilage degeneration, proteoglycan loss, and calcification of the joints, compared to wild-type controls [93]. Similarly, two surgically induced mouse models of osteoarthritis-one severe (partial meniscectomy) and one mild (joint destabilisation/injury)-suggest that ASK1 deficiency prevents cartilage damage and enhances bone repair [93].…”

“…Recent studies have associated ASK1-P38 and JNK with the damaging inflammatory responses underlying immunemediated disease, such as multiple sclerosis, amyotrophic lateral sclerosis, and arthritis [52,54,70,71,93].…”

“…Oxidative stress is strongly associated with chondrocyte hypertrophy, mediated by ASK1-P38 and JNK [105,106]. However, ASK1 inhibition using exogenous thioredoxin blocks the TNFR1-ASK1-P38/JNK signalling pathway in cultured synovial fibroblasts derived from human osteoarthritis knee tissue [93,106,107]. In vivo, chondrocyte hypertrophy is significantly reduced in untreated two-year-old Ask1 −/− mice, when compared to age-matched Ask1 +/+ mice [93].…”

“…However, ASK1 inhibition using exogenous thioredoxin blocks the TNFR1-ASK1-P38/JNK signalling pathway in cultured synovial fibroblasts derived from human osteoarthritis knee tissue [93,106,107]. In vivo, chondrocyte hypertrophy is significantly reduced in untreated two-year-old Ask1 −/− mice, when compared to age-matched Ask1 +/+ mice [93]. As a result, Ask1 −/− mice experience significantly less age-related cartilage degeneration, proteoglycan loss, and calcification of the joints, compared to wild-type controls [93].…”

“…As a result, Ask1 −/− mice experience significantly less age-related cartilage degeneration, proteoglycan loss, and calcification of the joints, compared to wild-type controls [93]. Similarly, two surgically induced mouse models of osteoarthritis-one severe (partial meniscectomy) and one mild (joint destabilisation/injury)-suggest that ASK1 deficiency prevents cartilage damage and enhances bone repair [93]. In the severe osteoarthritis model, wild-type mouse joints exhibit extensive cartilage degradation, proteoglycan loss, fibrosis, and inflammatory infiltrates at four weeks post surgery.…”