Chronic Pain after Bone Fracture: Current Insights into Molecular Mechanisms and Therapeutic Strategies

Abstract

Bone fracture following traumatic injury or due to osteoporosis is characterized by severe pain and motor impairment and is a major cause of global mortality and disability. Fracture pain often originates from mechanical distortion of somatosensory nerve terminals innervating bones and muscles and is maintained by central sensitization. Chronic fracture pain (CFP) after orthopedic repairs is considered one of the most critical contributors to interference with the physical rehabilitation and musculoskeletal functional recovery. Analgesics available for CFP in clinics not only have poor curative potency but also have considerable side effects; therefore, it is important to further explore the pathogenesis of CFP and identify safe and effective therapies. The typical physiopathological characteristics of CFP are a neuroinflammatory response and excitatory synaptic plasticity, but the specific molecular mechanisms involved remain poorly elucidated. Recent progress has deepened our understanding of the emerging properties of chemokine production, proinflammatory mediator secretion, caspase activation, neurotransmitter release, and neuron-glia interaction in initiating and sustaining synaptogenesis, synaptic strength, and signal transduction in central pain sensitization, indicating the possibility of targeting neuroinflammation to prevent and treat CFP. This review summarizes current literature on the excitatory synaptic plasticity, microgliosis, and microglial activation-associated signaling molecules and discusses the unconventional modulation of caspases and stimulator of interferon genes (STING) in the pathophysiology of CFP. We also review the mechanisms of action of analgesics in the clinic and their side effects as well as promising therapeutic candidates (e.g., specialized pro-resolving mediators, a caspase-6 inhibitor, and a STING agonist) for pain relief by the attenuation of neuroinflammation with the aim of better managing patients undergoing CFP in the clinical setting.

Keywords: STING; caspases; chronic fracture pain; neuroinflammation; spinal dorsal horn; synaptic plasticity.

Figure 1

Recent insights into the molecular mechanisms of chronic pain after fractures and orthopedic surgery. Pain injury from fractures and orthopedic surgery causes mechanical deformation of somatosensory nerve endings innervating bone and muscle, and the hyperexcitability of primary sensory neurons triggers the release of multiple cytokines from the presynaptic membrane of primary nociceptive sensory neurons, which are involved in CFP processes. These mainly include: (1) CCL21 released from presynaptic neurons acts on its specific receptor CXCR3 in microglia, which promotes TREM2/DAP12 complex formation and induces microglial activation; (2) the enhanced activity of caspase-6 in the presynaptic membrane can directly act on microglia to accelerate their activation, and it can also promote the release of Netrin-1 and promote the postsynaptic transport of AMPA receptors; (3) the increased secretion of glutamate-containing vesicles located in the presynaptic membrane into the synaptic cleft can positively regulate AMPA receptors or promote the phosphorylation of NMDA receptors to increase Ca²⁺ influx, and the increased secretion of CaMKII stimulates the expression of kalirin-7, which acts on IRE(-)DMT1 to promote Fe²⁺ influx and contributes to iron overload-related neurotoxicity; (4) CCL1 released from the presynaptic membrane can directly act on the specific receptor CCR8 located in the postsynaptic membrane, thereby promoting the phosphorylation of AMPA receptors and leading to central sensitization; (5) increased activity of caspase-3 in postsynaptic membrane promotes enhanced expression of LRRTM1, which is involved in AMPA receptor postsynaptic transport and synapse formation; (6) following the activation of microglial proliferation, a series of inflammatory factors are released that can directly increase excitatory synaptic transmission; (7) dsDNA stimulates cytoplasmic cGAS to produce cGAMP, which acts on the STING-TBK1-IRF-3 axis to promote clearance of pathogens and damaged host cells by inducing nuclear IFN-Is. The above series of reactions drive the process of central sensitization through the positive regulation of NMDA receptors or AMPA receptors or directly affect the transduction of excitatory signals at the postsynaptic membrane and participate in the development of the CFP process.