LPA/LPAR signaling drives temporomandibular disorders–like pain through regulating the expression and sensitization of PIEZO2
- Qiaojuan Zhang
- Shanchun Su
- Pengfei Liang
- Yun Chen
- Minseok Kim
- Robert Baldi
- Peng Wang
- Fabiana C. Dias
- Minji Jang
- Maria A. Gonzalez Torres
- Peifeng Lim
- Roger W.F. Moreira
- Jerold Chun
- Farshid Guilak
- Huanghe Yang
- Wolfgang Liedtke
- Andrea Nackley
- Yong Chen
2026-07-23
Temporomandibular disorders (TMD) pain is the most common orofacial pain with limited effective treatments. Here, we observed elevated lysophosphatidic acid (LPA), a bioactive lipid, in blood, trigeminal ganglion (TG), and peri-temporomandibular joint (TMJ) tissues in mouse models of TMD-like pain induced by TMJ inflammation or masseter muscle injury. Notably, LPA levels were also elevated in TMD patients’ blood and positively correlated with their pain intensity. LPA receptors (LPAR) 1 and 3 were expressed in mouse and human TG neurons and upregulated in TMD-like pain models. Inhibition or knockout of LPAR1 or LPAR3 attenuated TMD-like pain, while LPA injection into the TMJ or masseter muscle evoked pain. Furthermore, we demonstrated that LPA/LPAR signaling upregulates and sensitizes PIEZO2, a mechanosensitive ion channel, in TG neurons via extracellular signal-regulated kinase (ERK). Specific deletion or inhibition of PIEZO2 and suppression of ERK activation in TG neurons mitigated TMD-like pain. These findings suggest that LPA/LPAR signaling drives TMD-like pain via PIEZO2, offering potential therapeutic targets.