Acid-sensing ion channels mediate the degeneration of intervertebral disc via various pathways—A systematic review

Figures & data

Figure 1. Flowchart for identification and inclusion of relevant studies.

Table 1. Characteristics of included studies.

References	Authors	Researching Points		Journal
		ASICs	IVD
11	Yoshiyasu et al. 2007	ASIC3	NP	Journal of Bone and Mineral Research
12	Yoshiyasu et al. 2008	ASIC3	NP	Journal of Bone and Mineral Research
13	Antonio et al. 2014	ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, ASIC4	AF, NP	Connective Tissue Research
14	Li et al. 2014	ASIC1a	EP	Expert Opinion on Therapeutic Targets
15	Sun et al. 2014	ASIC1a, ASIC1b, ASIC3	NP	Acta Biochimica et Biophysica Sinica
16	Antonio et al. 2015	ASIC2a, ASIC2b	AF, NP	International Journal of Clinical and Experimental Pathology
17	Cai et al. 2016	ASIC1a	NP	Iranian Journal of Basic Medical Science
18	Gilbert et al. 2016	ASIC3	NP	Scientific Report
19	Yuan et al. 2016	ASIC1a	EP	Cell Stress and Chaperones
20	Xie et al. 2018	ASIC1a	NP	BioResearch Open Access
8	Wang et al. 2019	ASIC3	NP	Biomedicine & Pharmacotherapy

NOTE. ASIC, acid-sensing ion channel; IVD, intervertebral disc; NP, nucleus pulposus; EP, endplate; AF, annulus fibrosus.

Table 2. Expression changes of ASICs in intervertebral disc.

ASICs isotype	NP	AF	EP	Relative references
ASIC1a	↑	↑	→	[13,14,16,17,19]
ASIC1b	↑	↑	Unreported	[13, 15]
ASIC2a	↑	→	Unreported	[14,15]
ASIC2b	↑	→	Unreported	[14,15]
ASIC3	↑or↓	→	Unreported	[12,14,19]
ASIC4	↑	↑	Unreported	[14]

NOTE. ASIC, acid-sensing ion channel; NP, nucleus pulposus; AF, annulus fibrosus; EP, endplate; ↑, upregulation; ↓,downregulation; →, unchanged;

Table 3. Functional description of ASICs in intervertebral disc degeneration.

ASIC Isotypes	Functional Description	References
ASIC1a	ASIC1a activation in endplate chondrocytes may trigger Ca^2+-dependent protease activity and signaling, which leads to apoptosis of endplate chondrocytes in IVDs.	[13]
	ASIC1a activation induced the increased [Ca[^2]^+]i of NPCs, which resulted in cell apoptosis and stress-induced premature senesence.	[16]
	ASIC1a is involved in matrix metabolism of endplate chondrocytes under extracellular acidic conditions via NF-kB transcriptional activity.	[20]
	ASIC1a partly regulates ER stress and promotes apoptosis of NPCs under acid stimulus.	[17]
ASIC3	ASIC3 is needed for adaption of the NPCs and annulus fibrosus cells to the acidic and hyperosmotic microenvironment of the IVD.	[11]
	ASIC3 was involved in adapting disc cells to their hydrodynamically stressed microenvironment, suggesting an additional role for this ASIC subunit.	[19]
	Acidic pH causes a catabolic and degenerated phenotype in NPCs which is inhibited by blocking ASIC3 activity, suggesting that this may be a useful therapeutic target for treatment of IVD degeneration.	[18]
	ASIC3 over-expression inhibited the proliferation, arrested cell cycle in G1 phase, promoted the apoptosis in NPCs.	[8]

NOTE. ASIC, acid-sensing ion channel; IVD, intervertebral disc; NPC, nucleus pulposus cell.

Figure 2. Functional pathways of ASICs in IVDD.

ASIC1a mediates the degeneration of EP and NP by regulating the cellular metabolism and apoptosis process. ASIC3 promote the degeneration only in NP possibly via MAPK pathway and its pro-inflammatory function. Low pH is an acceptable up-stream promoter for ASICs’ expression, and SMAD, NGF, and HIF-1α are reported to be the regulator of ASIC3 in IVDD.

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