Targeted therapy for intervertebral disc degeneration: inhibiting apoptosis is a promising treatment strategy

Zhang, Xiaobo; Hu, Yi-Cun; Peng, Cheng; Zhou, Hai-Yu; Chen, Xiangyi; Wu, Duojie; Zhang, Ruihao; Yu, De-Chen; Gao, Xi-Dan; Shi, Jin-Tao; Zhang, Kai; Li, Shaolong; Song, Pengjie; Wang, Ke-Ping

doi:10.7150/ijms.59171

Cited by 48 publications

(33 citation statements)

References 115 publications

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“…The Fas death receptor is a therapeutic target for inhibiting apoptosis via the extrinsic pathway. A previous study has shown a reduction in apoptosis and improved annulus fibrosus cell proliferation with Fas-siRNA in a serum starvation model [99]. Bim, a member of the BH3 subfamily of the Bcl-2 family is also targeted for inhibiting apoptosis.…”

Section: Small Interfering Rna (Sirna)mentioning

confidence: 99%

Causes of and Molecular Targets for the Treatment of Intervertebral Disc Degeneration: A Review

Ohnishi

Iwasaki

Sudo

2022

Cells

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Intervertebral disc degeneration (IVDD) is a pathological condition that can lead to intractable back pain or secondary neurological deficits. There is no fundamental cure for this condition, and current treatments focus on alleviating symptoms indirectly. Numerous studies have been performed to date, and the major strategy for all treatments of IVDD is to prevent cell loss due to programmed or regulated cell death. Accumulating evidence suggests that several types of cell death other than apoptosis, including necroptosis, pyroptosis, and ferroptosis, are also involved in IVDD. In this study, we discuss the molecular pathway of each type of cell death and review the literature that has identified their role in IVDD. We also summarize the recent advances in targeted therapy at the RNA level, including RNA modulations through RNA interference and regulation of non-coding RNAs, for preventing cell death and subsequent IVDD. Therefore, we review the causes and possible therapeutic targets for RNA intervention and discuss the future direction of this research field.

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Section: Small Interfering Rna (Sirna)mentioning

confidence: 99%

Causes of and Molecular Targets for the Treatment of Intervertebral Disc Degeneration: A Review

Ohnishi

Iwasaki

Sudo

2022

Cells

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“…It is widely believed that IVD apoptosis and inflammatory response play important roles in the IVDD process. By studying the mechanisms of apoptosis and inflammatory response, targeting and regulating the specific mediating pathways provide hope for the treatment of IVDD [ 18 , 19 ]. Many studies have found that the caspase family is involved in the apoptosis and inflammatory response pathways and plays a crucial role [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Role of Caspase Family in Intervertebral Disc Degeneration and Its Therapeutic Prospects

Zhang

et al. 2022

Biomolecules

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Intervertebral disc degeneration (IVDD) is a common musculoskeletal degenerative disease worldwide, of which the main clinical manifestation is low back pain (LBP); approximately, 80% of people suffer from it in their lifetime. Currently, the pathogenesis of IVDD is unclear, and modern treatments can only alleviate its symptoms but cannot inhibit or reverse its progression. However, in recent years, targeted therapy has led to new therapeutic strategies. Cysteine-containing aspartate proteolytic enzymes (caspases) are a family of proteases present in the cytoplasm. They are evolutionarily conserved and are involved in cell growth, differentiation, and apoptotic death of eukaryotic cells. In recent years, it has been confirmed to be involved in the pathogenesis of various diseases, mainly by regulating cell apoptosis and inflammatory response. With continuous research on the pathogenesis and pathological process of IVDD, an increasing number of studies have shown that caspases are closely related to the IVDD process, especially in the intervertebral disc (IVD) cell apoptosis and inflammatory response. Therefore, herein we study the role of caspases in IVDD with respect to the structure of caspases and the related signaling pathways involved. This would help explore the strategy of regulating the activity of the caspases involved and develop caspase inhibitors to prevent and treat IVDD. The aim of this review was to identify the caspases involved in IVDD which could be potential targets for the treatment of IVDD.

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“…Thus, Wnt/β-catenin pathway activity plays a vital role in IVDD, and inhibition of the pathway by targeted therapy is an effective treatment. 23 Periostin (POSTN), an extracellular matrix (ECM) protein, is expressed in healthy tissues and has been used as a biomarker because it is aberrantly expressed in many diseases, such as asthma, 24,25 osteoarthritis, 26,27 and tumors. 28,29 POSTN is also expressed in IVDs and to be upregulated in IVDD.…”

Section: Introductionmentioning

confidence: 99%

Periostin promotes nucleus pulposus cells apoptosis by activating the Wnt/β‐catenin signaling pathway

et al. 2022

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Intervertebral disc (IVD) degeneration (IVDD) is closely linked to degenerative spinal disease, resulting in disability, poor quality of life, and financial burden. Apoptosis of nucleus pulposus (NP) cells (NPCs) is a key pathological basis of IVDD. Periostin (POSTN), an extracellular matrix protein, is expressed in many tissues, whereas its abnormal expression is associated with IVDD. The conventional Wnt/β‐catenin pathway is also involved in IVDD and contributes to NPCs apoptosis. However, research on the mechanisms of POSTN in IVDD is lacking. This study investigated the relationship between POSTN and β‐catenin expression in degenerated IVDs. We detected the expression of POSTN, β‐catenin, and cleaved‐caspase‐3 (C‐caspase3) in degenerated and non‐degenerated IVD tissues of different grades (n = 8) using RT‐qPCR, immunohistochemical staining, and western blotting analysis. Next, we explored the effects of recombinant periostin (rPOSTN) and isoquercitrin (Iso), an inhibitor of the Wnt/β‐catenin pathway, on NPCs apoptosis. Finally, we inhibited the expression of POSTN in degenerated NPCs in vivo and investigated the anti‐apoptotic effect. The expression of β‐catenin, POSTN, and C‐caspase3 in severe degenerative IVDs was significantly higher than that in mild degenerative IVDs. These findings were confirmed in rat and cell‐based degenerative models. When treated with rPOSTN, the Wnt/β‐catenin pathway activity and cell apoptosis were time‐ and dose‐dependent. However, rPOSTN‐induced NPCs apoptosis decreased after iso‐induced inhibition of the Wnt/β‐catenin pathway. POSTN inhibition reduced apoptosis but was restored by rPOSTN re‐addition. Lastly, POSTN inhibition ameliorated puncture‐induced IVDD in vivo. Overall, our study demonstrated that POSTN promotes NPCs apoptosis and aggravates degeneration by activating the Wnt/β‐catenin pathway.

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Targeted therapy for intervertebral disc degeneration: inhibiting apoptosis is a promising treatment strategy

Cited by 48 publications

References 115 publications

Causes of and Molecular Targets for the Treatment of Intervertebral Disc Degeneration: A Review

Causes of and Molecular Targets for the Treatment of Intervertebral Disc Degeneration: A Review

Role of Caspase Family in Intervertebral Disc Degeneration and Its Therapeutic Prospects

Periostin promotes nucleus pulposus cells apoptosis by activating the Wnt/β‐catenin signaling pathway

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