The Effects of Calcitonin Gene-Related Peptide on Bone Homeostasis and Regeneration

Xu, Jiankun; Wang, Jiali; Chen, Xiaodan; Li, Ye; Mi, Jie; Qin, Ling

doi:10.1007/s11914-020-00624-0

Cited by 58 publications

(46 citation statements)

References 110 publications

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“…In addition, as CGRP can directly affect osteoclastogenesis and osteoclasts play a crucial role in callus remodeling, osteoclasts may also engage in ES-enhanced fracture healing. [14,50] CGRP is described to distribute in nociceptive pathways in peripheral nervous system and its receptors are also expressed in pain pathways. [51] However, consistently with our present study, previous studies showed that increased local CGRP concentration at fracture site neither elevated the pain level nor induced aberrant sprouting of nerve fibers which can also cause pain.…”

Section: Discussionmentioning

confidence: 99%

“…[ 12 , 13 ] At the terminals of these nerves, CGRP is released following neuronal depolarization and then exerts its biological functions including angiogenesis and osteogenesis in bone regeneration. [ 14 , 15 , 16 ] Impaired release of CGRP at fracture sites retards fracture healing, leading to delayed fracture union and even nonunion, [ 17 ] while local supplementation of CGRP enhances the bone regeneration in bone defect. [ 14 , 15 , 18 , 19 ] Thus, CGRP is essential for fracture healing and may be a target for fracture healing enhancement.…”

Section: Introductionmentioning

confidence: 99%

“…[ 14 , 15 , 16 ] Impaired release of CGRP at fracture sites retards fracture healing, leading to delayed fracture union and even nonunion, [ 17 ] while local supplementation of CGRP enhances the bone regeneration in bone defect. [ 14 , 15 , 18 , 19 ] Thus, CGRP is essential for fracture healing and may be a target for fracture healing enhancement.…”

Section: Introductionmentioning

confidence: 99%

“…[ 3 ] In addition, as a peptide without quaternary structure of protein, CGRP degrades rapidly in plasma, which limits the application of exogenous CGRP in bone healing. [ 14 , 22 ] The endogenous CGRP is synthesized in dorsal root ganglion (DRG) and its transcription is highly regulated by depolarization. [ 23 ] We previously found that voltage‐controlled square unipolar pulse could increase the expression of CGRP in DRGs, [ 24 ] suggesting electrical stimulation (ES) at lumbar DRGs may increase endogenous CGRP for fracture healing.…”

Section: Introductionmentioning

confidence: 99%

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Implantable Electrical Stimulation at Dorsal Root Ganglions Accelerates Osteoporotic Fracture Healing via Calcitonin Gene‐Related Peptide

Yao

et al. 2021

Advanced Science

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The neuronal engagement of the peripheral nerve system plays a crucial role in regulating fracture healing, but how to modulate the neuronal activity to enhance fracture healing remains unexploited. Here it is shown that electrical stimulation (ES) directly promotes the biosynthesis and release of calcitonin gene-related peptide (CGRP) by activating Ca 2+ /CaMKII/CREB signaling pathway and action potential, respectively. To accelerate rat femoral osteoporotic fracture healing which presents with decline of CGRP, soft electrodes are engineered and they are implanted at L3 and L4 dorsal root ganglions (DRGs). ES delivered at DRGs for the first two weeks after fracture increases CGRP expression in both DRGs and fracture callus. It is also identified that CGRP is indispensable for type-H vessel formation, a biological event coupling angiogenesis and osteogenesis, contributing to ES-enhanced osteoporotic fracture healing. This proof-of-concept study shows for the first time that ES at lumbar DRGs can effectively promote femoral fracture healing, offering an innovative strategy using bioelectronic device to enhance bone regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Implantable Electrical Stimulation at Dorsal Root Ganglions Accelerates Osteoporotic Fracture Healing via Calcitonin Gene‐Related Peptide

Yao

et al. 2021

Advanced Science

Self Cite

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“…Sensory neurotransmitters such as calcitonin gene related peptide (CGRP) have previously been shown to promote bone formation in developing animals (Xu et al, 2020). By contrast, T1D can limit bone growth (Silva et al, 2009).…”

Section: Bone Lengthmentioning

confidence: 99%

Neuroskeletal Effects of Chronic Bioelectric Nerve Stimulation in Health and Diabetes

et al. 2021

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Background/AimsBioelectric nerve stimulation (eStim) is an emerging clinical paradigm that can promote nerve regeneration after trauma, including within the context of diabetes. However, its ability to prevent the onset of diabetic peripheral neuropathy (DPN) has not yet been evaluated. Beyond the nerve itself, DPN has emerged as a potential contributor to sarcopenia and bone disease; thus, we hypothesized that eStim could serve as a strategy to simultaneously promote neural and musculoskeletal health in diabetes.MethodsTo address this question, an eStim paradigm pre-optimized to promote nerve regeneration was applied to the sciatic nerve, which directly innervates the tibia and lower limb, for 8 weeks in control and streptozotocin-induced type 1 diabetic (T1D) rats. Metabolic, gait, nerve and bone assessments were used to evaluate the progression of diabetes and the effect of sciatic nerve eStim on neuropathy and musculoskeletal disease, while also considering the effects of cuff placement and chronic eStim in otherwise healthy animals.ResultsRats with T1D exhibited increased mechanical allodynia in the hindpaw, reduced muscle mass, decreased cortical and cancellous bone volume fraction (BVF), reduced cortical bone tissue mineral density (TMD), and decreased bone marrow adiposity. Type 1 diabetes also had an independent effect on gait. Placement of the cuff electrode alone resulted in altered gait patterns and unilateral reductions in tibia length, cortical BVF, and bone marrow adiposity. Alterations in gait patterns were restored by eStim and tibial lengthening was favored unilaterally; however, eStim did not prevent T1D-induced changes in muscle, bone, marrow adiposity or mechanical sensitivity. Beyond this, chronic eStim resulted in an independent, bilateral reduction in cortical TMD.ConclusionOverall, these results provide new insight into the pathogenesis of diabetic neuroskeletal disease and its regulation by eStim. Though eStim did not prevent neural or musculoskeletal complications in T1D, our results demonstrate that clinical applications of peripheral neuromodulation ought to consider the impact of device placement and eStim on long-term skeletal health in both healthy individuals and those with metabolic disease. This includes monitoring for compounded bone loss to prevent unintended consequences including decreased bone mineral density and increased fracture risk.

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Effects of Electric Field‐Modulated Conductive Hydrogel on Osseoperception and Osseointegration of Dental Implants

Qin,

Li,

Niu

et al. 2024

Adv Funct Materials

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Achieving optimal implant restoration hinges on both robust osseointegration as the structural foundation and favorable osseoperception for advanced masticatory function. The significance of nerve innervation in the peri‐implant environment as the cornerstone of osseointegration and osseoperception is often underestimated. Despite the integral role of endogenous electric fields (EFs) in the human body, particularly in electrosensitive tissues like nerve tissue, the current approach involving external electrical stimulation is invasive and not clinically applicable. The present study introduces a conductive hydrogel designed to respond to endogenous EFs, aiming to foster nerve regeneration around dental implants to coordinate both osseointegration and osseoperception. The hydrogel promotes neurite outgrowth by upregulating intracellular Ca2+ concentration and activating subsequent pathways. Furthermore, the enhanced release of neuropeptides from neurocells improves the osteogenesis of osteoblasts. The impact of the conductive hydrogel on osseointegration and osseoperception is also thoroughly investigated in vivo. This conductive hydrogel represents a unique strategy for enhancing osseointegration and osseoperception within the endogenous EFs of the peri‐implant environment. This advancement opens the door to achieving the physiological and psychological integration of dental implants.

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The Effects of Calcitonin Gene-Related Peptide on Bone Homeostasis and Regeneration

Cited by 58 publications

References 110 publications

Implantable Electrical Stimulation at Dorsal Root Ganglions Accelerates Osteoporotic Fracture Healing via Calcitonin Gene‐Related Peptide

Implantable Electrical Stimulation at Dorsal Root Ganglions Accelerates Osteoporotic Fracture Healing via Calcitonin Gene‐Related Peptide

Neuroskeletal Effects of Chronic Bioelectric Nerve Stimulation in Health and Diabetes

Effects of Electric Field‐Modulated Conductive Hydrogel on Osseoperception and Osseointegration of Dental Implants

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