Neuroinflammatory regulation of fracture healing after traumatic brain injury: Clinical evidence and emerging mechanistic insights

Table 3 Integrated neuroimmune and neuroendocrine factors regulating fracture healing after traumatic brain injury

Factor category	Key mediator(s)	TBI-related observation	Mechanism of action	Likely phase of action	Clinical/translational relevance
Neuropeptides	CGRP[37,41-43]	Elevated CGRP levels in serum after TBI correlate with accelerated fracture healing; CGRP may be released from brain tissue into serum; α-CGRP deficiency leads to impaired callus bridging, reduced osteoblast numbers, and high rate of non-union	Promotes osteoblast proliferation and differentiation via cAMP signaling pathway; modulates bone remodeling through CGRP receptor (CRLR/RAMP1) activation; induces expression of genes linked to ossification and bone remodeling	Inflammatory and reparative phases	CGRP receptor agonism represents potential therapeutic approach to stimulate bone regeneration; neurologic regulation of bone metabolism
Neuropeptides	VIP[16,44-45]	No direct TBI-related evidence; however, VIP exhibits context-dependent effects on fracture healing and may interact with altered sympathetic tone	Promotes BMSC osteogenic differentiation via activation of Wnt/β-catenin signaling; interacts with neuroendocrine environment	Reparative phase	Potential therapeutic candidate for bone regeneration; biomaterial-based delivery may enhance repair, but efficacy depends on local neuroendocrine and sympathetic status
Neurotrophins	NGF[46-50]	Elevated in serum and fracture callus after TBI	Promotes osteogenic differentiation via NGF-TrkA signaling and MEK/ERK pathway; enhances VEGF-mediated angiogenesis	Reparative phase	NGF delivery systems may enhance fracture healing in polytrauma patients
Neuroendocrine hormones	GH/IGF-1 axis[13,15,51-53]	TBI patients exhibit elevated circulating GH during early fracture healing; associated with accelerated callus formation[20]	GH promotes osteoblast differentiation and matrix deposition primarily via IGF-1 pathway	Early inflammatory and reparative phases	Monitoring GH levels may predict healing outcomes[20]; potential therapeutic window despite hypopituitarism risk
Neuroendocrine hormones	PTH[13,20,54]	Elevated circulating PTH in TBI patients during early fracture healing	Intermittent PTH signaling enhances callus formation and endochondral ossification; creates systemic osteoanabolic environment	Early inflammatory and reparative phase	Potential therapeutic agent for impaired fracture healing; exogenous PTH 1-34 can rescue deficient bone repair
Neuroendocrine hormones	Leptin[15,55]	Leptin levels are elevated in serum and cerebrospinal fluid after TBI, positively correlated with GH and IGF-1, and associated with accelerated callus formation	Leptin signaling appears necessary for TBI-induced acceleration of fracture healing; involved in regulation of energy metabolism, fat storage, and bone homeostasis	Early inflammatory and reparative phases	Intact leptin signaling is critical for TBI-mediated bone regeneration
Sympathetic nervous system	Norepinephrine/β2-AR signaling[9,10]	TBI induces hyperadrenergic state with elevated sympathetic tone; increased norepinephrine in bone tissue	Norepinephrine stimulates VEGF-A and CGRP-α expression in periosteal cells via β2-AR; promotes type-H vessel formation and callus neovascularization	Early inflammatory and reparative phases	β2-AR agonists (formoterol) accelerate healing; β-blockers (propranolol) impair healing; intravenous norepinephrine in trauma patients shows improved callus formation
Pro-inflammatory cytokines	IL-6[20,61-64]	Complex biphasic pattern; classical signaling essential early; local blockade accelerates healing in specific contexts	Early classical IL-6 signaling promotes inflammation and immune cell recruitment; local IL-6 blockade modulates CGRP activity, reduces TNF-α/IL-1β, promotes M2 polarization	Context-dependent: Early inflammatory vs late reparative phases	IL-6 functions as immunoregulatory switch; timing and location of intervention critical; local vs systemic effects differ
Pro-inflammatory cytokines	IL-1β[6,9]	Serum levels significantly elevated at 12 hours and 4 weeks in TBI + fracture patients	Initiates early inflammatory cascade essential for fracture repair; regulated by TBI-induced sympathetic-immune axis favoring M2 macrophage polarization	Early inflammatory phase (with sustained elevation through 4 weeks)	Elevated IL-1β at early and late timepoints associated with accelerated healing; reflects TBI-mediated immunomodulation toward pro-regenerative state
Growth factors	BMP-2[6]	Significantly elevated in serum at 12 hours and 4 weeks in TBI + fracture patients	Promotes osteoblast differentiation and bone formation; likely enhanced by TBI-induced sympathetic-mediated anti-inflammatory microenvironment	Early inflammatory and reparative phases	Elevated BMP-2 associated with accelerated fracture healing in TBI patients; potential biomarker for healing trajectory
Growth factors	PDGF[6]	Serum levels significantly elevated at 12 hours and 4 weeks in TBI + fracture patients	Stimulates mesenchymal cell proliferation and migration; enhanced by TBI-mediated sympathetic activation and anti-inflammatory environment	Early inflammatory and reparative phases	Elevated PDGF associated with healing acceleration; potential therapeutic target
Growth factors	FGF-2[6]	Serum levels significantly elevated at 12 hours and 4 weeks in TBI + fracture patients	Promotes angiogenesis and mesenchymal cell proliferation; operates within TBI-induced pro-regenerative microenvironment shaped by sympathetic tone	Early inflammatory and reparative phases	FGF-2 elevation may serve as predictor of enhanced healing in TBI + fracture patients

TBI: Traumatic brain injury; CGRP: Calcitonin gene-related peptide; cAMP: Cyclic adenosine monophosphate; CRLR: Calcitonin receptor-like receptor; RAMP1: Receptor activity-modifying protein 1; VIP: Vasoactive intestinal peptide; BMSC: Bone marrow mesenchymal stem cells; Wnt: Wingless-related integration site; NGF: Nerve growth factor; TrkA: Tropomyosin receptor kinase A; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; VEGF-A: Vascular endothelial growth factor A; GH: Growth hormone; IGF-1: Insulin-like growth factor 1; PTH: Parathyroid hormone; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; BMP-2: Bone morphogenetic protein 2; PDGF: Platelet-derived growth factor; FGF-2: Fibroblast growth factor 2.