Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats

Glaeser, Juliane D.; Ju, Derek G; Tawackoli, Wafa; Yang, Jae Hyuk; Salehi, Khosrowdad; Stefanovic, Tina; Kanim, Linda E.A.; Avalos, Pablo; Kaneda, Giselle; Stephan, Stephen; Metzger, Melodie F.; Sheyn, Dmitriy

doi:10.3390/ijms21249709

Cited by 11 publications

(9 citation statements)

References 53 publications

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“…Histological analysis of injected IVDs (L4/5, L5/L6 levels) of all tested groups showed no visible disc degeneration compared to reported degeneration models ( 47, 64, 65 ) 8 weeks post intradiscal injection (Fig. 6E).…”

Section: Resultsmentioning

confidence: 87%

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Jiang

Glaeser

Kaneda

et al. 2023

Preprint

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Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing nucleus pulposus cells (NPCs), generated by the environmental stress in degenerating discs, that triggered the onset of discogenic LBP. Single-cell transcriptomic analysis of human tissues showed a strong correlation between this specific pain-triggering subtype and the pain conditions in human degenerated discs. Next, we recreated this pain-triggering subtype by applying known exogenous stressors to healthy NPCsin vitro. The recreated pain phenotype activated functional sensory neurons responsein vitroand induced local inflammatory responses, hyperalgesia, and mechanical sensitivity in a healthy rat IVDin vivo. Our findings provide strong evidence of a previously unknown pain-inducing mechanism mediated by NPCs in degenerating IVDs. This newly defined pathway will aid in the development of NPC-targeted therapeutic strategies for clinically unmet need to attenuate discogenic LBP.One Sentence SummaryDiscogenic low back pain can be initiated by a stress-induced subtype of nucleus pulposus cells present in human degenerating intervertebral discs

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Section: Resultsmentioning

confidence: 87%

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Jiang

Glaeser

Kaneda

et al. 2023

Preprint

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“…Histological analysis of IVDs (L4/5 and L5/L6 levels) at 8 weeks after intradiscal injection showed no visible disc degeneration ( 47 , 75 , 76 ) in any of the treatment groups (Fig. 5E).…”

Section: Resultsmentioning

confidence: 96%

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats

Jiang,

Glaeser,

Kaneda

et al. 2023

Sci. Transl. Med.

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Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.

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“…MRI image analysis showed that oral treatment with the AGE inhibitor PM could reduce NP dehydration after needle injury. PM also promoted the increase in the level of oligosaccharides in rats ( 75 ). In addition, AGEs-BSA can induce mitochondrial damage in NP cells through activation of NLRP3 inflammatory bodies, resulting in a secondary inflammatory response ( 76 ).…”

Section: Abnormal Glucose Metabolism and Iddmentioning

confidence: 95%

From hyperglycemia to intervertebral disc damage: exploring diabetic-induced disc degeneration

Li,

Du,

Huang

et al. 2024

Front. Immunol.

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The incidence of lumbar disc herniation has gradually increased in recent years, and most patients have symptoms of low back pain and nerve compression, which brings a heavy burden to patients and society alike. Although the causes of disc herniation are complex, intervertebral disc degeneration (IDD) is considered to be the most common factor. The intervertebral disc (IVD) is composed of the upper and lower cartilage endplates, nucleus pulposus, and annulus fibrosus. Aging, abnormal mechanical stress load, and metabolic disorders can exacerbate the progression of IDD. Among them, high glucose and high-fat diets (HFD) can lead to fat accumulation, abnormal glucose metabolism, and inflammation, which are considered important factors affecting the homeostasis of IDD. Diabetes and advanced glycation end products (AGEs) accumulation- can lead to various adverse effects on the IVD, including cell senescence, apoptosis, pyroptosis, proliferation, and Extracellular matrix (ECM) degradation. While current research provides a fundamental basis for the treatment of high glucose-induced IDD patients. further exploration into the mechanisms of abnormal glucose metabolism affecting IDD and in the development of targeted drugs will provide the foundation for the effective treatment of these patients. We aimed to systematically review studies regarding the effects of hyperglycemia on the progress of IDD.

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Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats

Cited by 11 publications

References 53 publications

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats

From hyperglycemia to intervertebral disc damage: exploring diabetic-induced disc degeneration

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