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Proton-activated chloride channel increases endplate porosity and pain in a mouse spine degeneration model
Peng Xue, … , Zhaozhu Qiu, Xu Cao
Peng Xue, … , Zhaozhu Qiu, Xu Cao
Published August 28, 2024
Citation Information: J Clin Invest. 2024;134(20):e168155. https://doi.org/10.1172/JCI168155.
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Research Article Bone biology Cell biology

Proton-activated chloride channel increases endplate porosity and pain in a mouse spine degeneration model

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Abstract

Chronic low back pain (LBP) can severely affect daily physical activity. Aberrant osteoclast-mediated resorption leads to porous endplates, which allow the sensory innervation that causes LBP. Here, we report that expression of the proton-activated chloride (PAC) channel was induced during osteoclast differentiation in the porous endplates via a RANKL/NFATc1 signaling pathway. Extracellular acidosis evoked robust PAC currents in osteoclasts. An acidic environment of porous endplates and elevated PAC activation–enhanced osteoclast fusion provoked LBP. Furthermore, we found that genetic knockout of the PAC gene Pacc1 significantly reduced endplate porosity and spinal pain in a mouse LBP model, but it did not affect bone development or homeostasis of bone mass in adult mice. Moreover, both the osteoclast bone-resorptive compartment environment and PAC traffic from the plasma membrane to endosomes to form an intracellular organelle Cl channel had a low pH of approximately 5.0. The low pH environment activated the PAC channel to increase sialyltransferase St3gal1 expression and sialylation of TLR2 in the initiation of osteoclast fusion. Aberrant osteoclast-mediated resorption is also found in most skeletal disorders, including osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, heterotopic ossification, and enthesopathy. Thus, elevated Pacc1 expression and PAC activity could be a potential therapeutic target for the treatment of LBP and osteoclast-associated pain.

Authors

Peng Xue, Weixin Zhang, Mengxi Shen, Junhua Yang, Jiachen Chu, Shenyu Wang, Mei Wan, Junying Zheng, Zhaozhu Qiu, Xu Cao

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Figure 1

Knockout of Pacc1 significantly reduces spinal pain and endplate porosity in a mouse model of spine degeneration.

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Knockout of Pacc1 significantly reduces spinal pain and endplate porosit...
(A) Pressure tolerance of the lumbar spine as assessed by the force threshold needed to induce vocalization by a force gauge 4 and 8 weeks after LSI surgery. (B) Hind PWF in response to mechanical stimulation (von Frey, 0.4 g) 4 and 8 weeks after LSI surgery. (C and D) Spontaneous activity analysis, including distance traveled (C) and active time (D) on the wheel per 24-hour period. (E) Representative 3D, high-resolution μCT images of the L4–L5 caudal endplates (coronal view) 8 weeks after LSI surgery (n = 6 per group). Scale bar: 1 mm. (F and G) Quantitative analysis of total porosity (F) and trabecular separation (Tb.Sp) (G) of the L4–L5 caudal endplates as determined by μCT. (H) Representative images of CGRP (red) and DAPI (blue) immunofluorescence staining of nerve fibers in the endplates 8 weeks after LSI surgery. Scale bar: 50 μm. (I) Representative images of SOFG staining of coronal L4–L5 caudal endplate sections 8 weeks after LSI surgery. Scale bar: 50 μm. (J) Quantitative analysis of the area of cartilage in the endplates of Pacc1+/+ and Pacc1–/– mice 8 weeks after LSI surgery. (K) Representative images of coronal L4–L5 caudal endplate sections stained for TRAP 8 weeks after LSI surgery. Scale bar: 50 μm. (L) Quantitative analysis of the number of TRAP+ multinuclear cells in endplates. N.Mu., number of multinuclear osteoclasts; OC, osteoclast; B.Pm, bone perimeter. (A–D, F, and G) *P < 0.05 compared with the sham group; #P < 0.05 compared with Pacc1+/+ mice after LSI surgery (n = 6 per group). (J and L) *P < 0.05 compared with the Pacc1+/+ group, by 1-way ANOVA (A, D, F, and F) and 2-tailed t test (J and L) (n = 6 per group). Data are presented as the mean ± SD.

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