Proton-activated chloride channel increases endplate porosity and pain in a mouse spine degeneration model
Peng Xue, Weixin Zhang, Mengxi Shen, Junhua Yang, Jiachen Chu, Shenyu Wang, Mei Wan, Junying Zheng, Zhaozhu Qiu, Xu Cao
Peng Xue, Weixin Zhang, Mengxi Shen, Junhua Yang, Jiachen Chu, Shenyu Wang, Mei Wan, Junying Zheng, Zhaozhu Qiu, Xu Cao
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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

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 6

PAC-mediated ICl, H current activity in response to extracellular acidosis enhances osteoclast fusion and resorption.

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PAC-mediated ICl, H current activity in response to extracellular acidos...
(A and B) Resorption pits of the cells isolated from Pacc1+/+ and Pacc1–/– mice; cells were cultured in neural or acidic medium at day 7 (n = 3). Scale bar: 50 μm. (C) PAC-mediated currents in single cells (osteoclast precursors) or fused cells (mature osteoclasts) cultured in osteoclastic medium for 3 days (n ≥7). (D) PAC-mediated currents in the cells cultured in osteoclastic medium for 3 or 5 days (n ≥7). (E and G) TRAP staining of cells isolated from Pacc1+/+ and Pacc1–/– mice; cells were cultured in neural or acidic medium at day 3 and day 5 (n = 3). Scale bar: 50 μm. (F and H) Phalloidin staining for cells isolated from Pacc1+/+ or Pacc1–/– mice cultured in neural or acidic medium at 3 and 5 days (n = 3). Scale bar: 50 μm. (B, G, and H) *P < 0.05 compared with cells isolated from Pacc1+/+ mice cultured in the neutral medium; #P < 0.05 compared with cells isolated from Pacc1+/+ mice cultured in the acidic medium. (C) *P < 0.05 compared with the single cell. (D) *P < 0.05 compared with day 3. Significance was determined by 1-way ANOVA (A, B, G, and H) and 2-tailed t test (C and D). Data are presented as the mean ± SD.