Insights into the underlying pathogenesis and therapeutic potential of endoplasmic reticulum stress in degenerative musculoskeletal diseases

Abstract

Degenerative musculoskeletal diseases are structural and functional failures of the musculoskeletal system, including osteoarthritis, osteoporosis, intervertebral disc degeneration (IVDD), and sarcopenia. As the global population ages, degenerative musculoskeletal diseases are becoming more prevalent. However, the pathogenesis of degenerative musculoskeletal diseases is not fully understood. Previous studies have revealed that endoplasmic reticulum (ER) stress is a stress response that occurs when impairment of the protein folding capacity of the ER leads to the accumulation of misfolded or unfolded proteins in the ER, contributing to degenerative musculoskeletal diseases. By affecting cartilage degeneration, synovitis, meniscal lesion, subchondral bone remodeling of osteoarthritis, bone remodeling and angiogenesis of osteoporosis, nucleus pulposus degeneration, annulus fibrosus rupture, cartilaginous endplate degeneration of IVDD, and sarcopenia, ER stress is involved in the pathogenesis of degenerative musculoskeletal diseases. Preclinical studies have found that regulation of ER stress can delay the progression of multiple degenerative musculoskeletal diseases. These pilot studies provide foundations for further evaluation of the feasibility, efficacy, and safety of ER stress modulators in the treatment of musculoskeletal degenerative diseases in clinical trials. In this review, we have integrated up-to-date research findings of ER stress into the pathogenesis of degenerative musculoskeletal diseases. In a future perspective, we have also discussed possible directions of ER stress in the investigation of degenerative musculoskeletal disease, potential therapeutic strategies for degenerative musculoskeletal diseases using ER stress modulators, as well as underlying challenges and obstacles in bench-to-beside research.

Trial registration: ClinicalTrials.gov NCT03533257 NCT02046434.

Keywords: Degenerative musculoskeletal diseases; Endoplasmic reticulum stress; Pathogenesis; Treatment.

Fig. 1

Mechanisms of the UPR (a) and ERAD (b) pathways. ATF4 activating transcription factor 4, ATF6 activating transcription factor 6, BiP binding immunoglobulin protein, CHOP C/EBP homologous protein, eIF2α α-subunit of eukaryotic translation initiation factor 2, ER endoplasmic reticulum, ERAD ER-associated degradation, GADD34 growth arrest and DNA damage-inducible protein 34, IRE1 inositol-requiring enzyme 1, P phosphorylated, PERK protein kinase R-like ER kinase, S1P site-1 membrane proteases, S2P site-2 membrane proteases, XBP-1 X-binding protein 1, XBP-1s spliced XBP-1, Ub ubiquitin

Fig. 2

ER stress in the pathogenesis of OA. a Pathological changes in OA regulated by ER stress. b IRE1-mTORC1-PERK signaling pathway synergistically regulates autophagy and apoptosis in OA chondrocytes. Attenuation of IRE1 signaling activates mTORC1, converting protective autophagy to apoptosis. c Mechanisms through which ER stress accelerates OA progression in synovitis. A vicious cycle of HIF-1α-GLUT1-AGEs-HIF-1α may exist in the fibroblast-like synoviocyte of patients with diabetes-related OA, aggravating OA progression. d ER stress is involved in meniscal lesion to accelerate OA progression. Palmitate degrades ATG5 through the ERAD pathway to inhibit autophagy and promote meniscus cell apoptosis. AGEs advanced glycation end products, ATG5 autophagy-related 5, ER endoplasmic reticulum, ERAD ER-associated degradation, GLUT1 glucose transporter 1, HIF-1α hypoxia-inducible factor-1α, IRE1 inositol-requiring enzyme 1, mTORC1 mechanistic target of rapamycin complex 1, OA osteoarthritis, PERK protein kinase R-like ER kinase, RAGE receptor for AGEs

Fig. 3

ER stress in the pathogenesis of OP. a Bone remodeling is mainly regulated by the coupling of osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and osteocytes have also been reported to participate in bone remodeling in OP. b RANKL activates CREBH through ROS/ER stress signaling pathway to promote the transcription of NFATc1, ultimately leading to increased osteoclastogenesis. c Autophagy deficiency induced by conditional Atg7 deletion inhibits mineralization and promotes ER stress and apoptosis in osteoblasts. CHOP C/EBP homologous protein, CREBH cAMP response element-binding protein H, C/EBPβ CCAAT/enhancer binding protein β, eIF2α α-subunit of eukaryotic translation initiation factor 2, ER endoplasmic reticulum, IRE1 inositol-requiring enzyme 1, MAPK8 mitogen-activated protein kinase 8, NFATc1 nuclear factor of activated T cells cytoplasmic 1, PERK protein kinase R-like ER kinase, RANKL receptor activator of NF-κB ligand, ROS reactive oxygen species, Runx2 Runt-related transcription factor 2, S1P site-1 membrane proteases, S2P site-2 membrane proteases, Smad small mother against decapentaplegic

Fig. 4

ER stress in the pathogenesis of IVDD. a Pathological changes of IVDD involved by ER stress. b The mechanisms by which ER stress promotes IVDD progression through aggravating NP degeneration. IP3R is located on ER, VDAC1 is a mitochondrial outer membrane protein, and GRP75 is a connexin, which can link IP3R to VDAC1 to form a channel for Ca²⁺ translocation. AF annulus fibrosus, AGEs advanced glycation end products, AIF apoptosis-inducing factor, CEP cartilaginous endplate, ER endoplasmic reticulum, GRP75 glucose-regulated protein 75, IP3R inositol 1,4,5-trisphosphate receptor, IVDD intervertebral disc degeneration, mSREBP mature form of SREBP1, NP nucleus pulposus, PARP poly(ADP-ribose) polymerase, RyR ryanodine receptor, SERCA sarco/endoplasmic reticulum Ca²⁺-ATPase, SREBP sterol response element binding protein, S1P site-1 membrane proteases, S2P site-2 membrane proteases, VDAC1 voltage-dependent anion-selective channel 1

Fig. 5

ER stress in the pathogenesis of sarcopenia (SP). a Schematic illustration of SP. b FABP3-dependent membrane lipid remodeling and decreased membrane fluidity result in ER stress and inhibit protein translation through the PERK-eIF2α pathway, ultimately leading to SP. eIF2α α-subunit of eukaryotic translation initiation factor 2, ER endoplasmic reticulum, FA fatty acid, FABP3 fatty acid binding protein 3, PERK protein kinase R-like ER kinase