Spinal 7-dehydrocholesterol reductase dependent cholesterol overload regulates astrocyte activation and mGluR5/ERK cascades via monocyte chemotactic protein 3 in tibial fracture-induced chronic pain in mice

  • Neurosci Res. 2026 Jun:227:105064. doi: 10.1016/j.neures.2026.105064.
Chao Qi  1 ,  Jian Zhao  2 ,  Donghui Guo  3 ,  Shiqiang Ma  3 ,  Hengjun Wang  3 ,  Xingyue Wang  3 ,  Hao Zhou  3 ,  Zhenhui Huo  3 ,  Xiaoming Li  3 ,  Xin Fu  4 ,  Jun Liu  5
Affiliations
  • 1. Clinical College of Orthopedics, Tianjin Medial University, Tianjin, China; Department of Joints, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine in Hebei Province, Cangzhou, Hebei, China; Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research, Cangzhou, Hebei, China.
  • 2. Medical Imaging Department, Hebei Provincial Children Hospital, Shijiazhuang, Hebei, China.
  • 3. Department of Joints, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine in Hebei Province, Cangzhou, Hebei, China; Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research, Cangzhou, Hebei, China.
  • 4. Clinical College of Orthopedics, Tianjin Medial University, Tianjin, China; Department of Joints, Tianjin Hospital, Tianjin, China.
  • 5. Clinical College of Orthopedics, Tianjin Medial University, Tianjin, China; Department of Joints, Tianjin Hospital, Tianjin, China. Electronic address: [email protected].
PMID: 42069085 DOI: 10.1016/j.neures.2026.105064
Abstract

Patients with bone fractures commonly experience an exasperating and long-lasting pain following orthopedic procedures. Spinal monocyte chemotactic protein 3 (MCP-3)-encoding astrogliosis and mGluR5-mediated excitatory synaptic plasticity are essential for central nociceptive transmission. Recent studies highlight the requirement of 7-dehydrocholesterol reductase (DHCR7) for Cholesterol overload and neuroinflammation. This present study investigates the potential associations among DHCR7, MCP-3 and mGluR5 in chronic pain using a mouse model of tibial fracture with intramedullary pinning. Here, we report that tibial fracture and orthopedic repairs induce persistent mechanical and cold allodynia, along with spinal Cholesterol accumulation and increased expression of DHCR7. Spinal (intrathecal) therapies with DHCR7 inhibitor AY9944 prevent and ameliorate persistent pain after fracture surgeries. Moreover, AY9944 reduces spinal Cholesterol overload, MCP-3 secretion, astrocyte activation and increased expression of mGluR5 in fracture mice. Spinal administration of mGluR5 Antagonist MPEP is protective against fracture-associated allodynia by decreasing ERK phosphorylation. Strikingly, AY9944 caused the attenuation of behavioral allodynia and astrocyte activation were eliminated after exogenous MCP-3 co-administration. Additionally, spinal neutralization of MCP-3 relieved persistent pain behaviors, astrocyte activation and increased expression of mGluR5 following fractures. Astrocytic inhibitor fluorocitrate reduced chronic fracture pain. Collectively, these findings uncover that spinal DHCR7-mediated Cholesterol overload is an important pathogenesis of fracture-associated chronic allodynia by modulating MCP-3-dependent astrocyte activation, mGluR5 expression and ERK phosphorylation.

Keywords
Astrocyte activation; Cholesterol overload; Chronic fracture pain; DHCR7; MCP-3.
Products