Calcitonin Gene-Related Peptide Influences Bone-Tendon Interface Healing Through Osteogenesis: Investigation in a Rabbit Partial Patellectomy Model

Overview

Journal Orthop J Sports Med

Specialty Orthopedics

Date 2021 Aug 4

PMID 34345631

Citations 7

Authors

Huabin Chen

Hongbin Lu

Jianjun Huang

Zhanwen Wang

Yang Chen

Tao Zhang

Affiliations

Soon will be listed here.

Abstract

Background: Calcitonin gene-related peptide (CGRP), which has been shown to play an important role in osteogenesis during fracture repair, is also widely distributed throughout the tendon and ligament. Few studies have focused on the role of CGRP in repair of the bone-tendon interface (BTI).

Purpose: To explore the effect of CGRP expression on BTI healing in a rabbit partial patellectomy model.

Study Design: Controlled laboratory study.

Methods: A total of 60 mature rabbits were subjected to a partial patellectomy and then randomly assigned to CGRP, CGRP-antagonist, and control groups. In the CGRP-antagonist group, the CGRP receptor antagonist BIBN4096BS was administered to block CGRP receptors. The patella-patellar tendon complex was harvested at 8 and 16 weeks postoperatively and subjected to radiographic, microlaser Raman spectroscopy, histologic, and biomechanical evaluation.

Results: Radiographic data showed that local CGRP expression improved the growth parameters of newly formed bone, including area and volumetric bone mineral density ( < .05 for both). Raman spectroscopy revealed that the relative bone mineral composition increased in the CGRP group compared with in the control group and the CGRP-antagonist group ( < .05 for both). Histologic testing revealed that the CGRP group demonstrated better integration, characterized by well-developed trabecular bone expansion from the residual patella and marrow cavity formation, at the 8- and 16-week time points. Mechanical testing demonstrated that the failure load, ultimate strength, and stiffness in the CGRP group were significantly higher than those in the control group ( < .05 for all), whereas these parameters in the CGRP-antagonist group were significantly lower compared with those in the control group at 16 weeks after surgery ( < .05 for all).

Conclusion: Increasing the local concentration of CGRP in the early stages of BTI healing enhanced osteogenesis in a rabbit partial patellectomy model and promoted healing of the BTI injury, whereas treatment using a CGRP antagonist had the opposite effect. However, exogenous CGRP expression did not induce novel bone remolding.

Clinical Relevance: CGRP may have potential as a new therapy for BTI injuries or may be added to postoperative regimens to facilitate healing.

Citing Articles

Predictive Neuromarker Patterns for Calcification Metaplasia in Early Tendon Healing.

Faydaver M, Festinese V, Di Giacinto O, El Khatib M, Raspa M, Scavizzi F Vet Sci. 2024; 11(9).

PMID: 39330820 PMC: 11435825. DOI: 10.3390/vetsci11090441.

Activation of CGRP receptor-mediated signaling promotes tendon-bone healing.

Zhao X, Wu G, Zhang J, Yu Z, Wang J Sci Adv. 2024; 10(10):eadg7380.

PMID: 38457499 PMC: 10923525. DOI: 10.1126/sciadv.adg7380.

Do Not Lose Your Nerve, Be Callus: Insights Into Neural Regulation of Fracture Healing.

Nazzal M, Morris A, Parker R, White F, Natoli R, Kacena M Curr Osteoporos Rep. 2024; 22(1):182-192.

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Cracking the Code: The Role of Peripheral Nervous System Signaling in Fracture Repair.

Morris A, Parker R, Nazzal M, Natoli R, Fehrenbacher J, Kacena M Curr Osteoporos Rep. 2024; 22(1):193-204.

PMID: 38236511 PMC: 10912155. DOI: 10.1007/s11914-023-00846-y.

Role of the Neurologic System in Fracture Healing: An Extensive Review.

Parker R, Nazzal M, Morris A, Fehrenbacher J, White F, Kacena M Curr Osteoporos Rep. 2024; 22(1):205-216.

PMID: 38236509 PMC: 10912173. DOI: 10.1007/s11914-023-00844-0.

References

Zhou Y, Zhang H, Zhang G, He Y, Zhang P, Sun Z . Calcitonin gene‑related peptide reduces Porphyromonas gingivalis LPS‑induced TNF‑α release and apoptosis in osteoblasts. Mol Med Rep. 2017; 17(2):3246-3254. DOI: 10.3892/mmr.2017.8205. View

He H, Chai J, Zhang S, Ding L, Yan P, Du W . CGRP may regulate bone metabolism through stimulating osteoblast differentiation and inhibiting osteoclast formation. Mol Med Rep. 2016; 13(5):3977-84. DOI: 10.3892/mmr.2016.5023. View

Irie K, Ozawa H, Yajima T . Calcitonin gene-related peptide (CGRP)-containing nerve fibers in bone tissue and their involvement in bone remodeling. Microsc Res Tech. 2002; 58(2):85-90. DOI: 10.1002/jemt.10122. View

Cadosch D, Gautschi O, Thyer M, Song S, Skirving A, Filgueira L . Humoral factors enhance fracture-healing and callus formation in patients with traumatic brain injury. J Bone Joint Surg Am. 2009; 91(2):282-8. DOI: 10.2106/JBJS.G.01613. View

Agout C, Berhouet J, Bouju Y, Godeneche A, Collin P, Kempf J . Clinical and anatomic results of rotator cuff repair at 10 years depend on tear type. Knee Surg Sports Traumatol Arthrosc. 2018; 26(8):2490-2497. DOI: 10.1007/s00167-018-4854-1. View

Wang L, Shi X, Zhao R, Halloran B, Clark D, Jacobs C . Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-kappaB activation, osteoclastogenesis and bone resorption. Bone. 2009; 46(5):1369-79. PMC: 2854244. DOI: 10.1016/j.bone.2009.11.029. View

Lu H, Qin L, Fok P, Cheung W, Lee K, Guo X . Low-intensity pulsed ultrasound accelerates bone-tendon junction healing: a partial patellectomy model in rabbits. Am J Sports Med. 2006; 34(8):1287-96. DOI: 10.1177/0363546506286788. View

Lu H, Qin L, Cheung W, Lee K, Wong W, Leung K . Low-intensity pulsed ultrasound accelerated bone-tendon junction healing through regulation of vascular endothelial growth factor expression and cartilage formation. Ultrasound Med Biol. 2008; 34(8):1248-60. DOI: 10.1016/j.ultrasmedbio.2008.01.009. View

Xu D, Zhang T, Qu J, Hu J, Lu H . Enhanced patella-patellar tendon healing using combined magnetic fields in a rabbit model. Am J Sports Med. 2014; 42(10):2495-501. DOI: 10.1177/0363546514541539. View

10.

Kawakami Y, Takayama K, Matsumoto T, Tang Y, Wang B, Mifune Y . Anterior Cruciate Ligament-Derived Stem Cells Transduced With BMP2 Accelerate Graft-Bone Integration After ACL Reconstruction. Am J Sports Med. 2016; 45(3):584-597. DOI: 10.1177/0363546516671707. View

11.

Tuzmen C, Verdelis K, Weiss L, Campbell P . Crosstalk between substance P and calcitonin gene-related peptide during heterotopic ossification in murine Achilles tendon. J Orthop Res. 2017; 36(5):1444-1455. PMC: 6449576. DOI: 10.1002/jor.23833. View

12.

Schlundt C, Khassawna T, Serra A, Dienelt A, Wendler S, Schell H . Macrophages in bone fracture healing: Their essential role in endochondral ossification. Bone. 2015; 106:78-89. DOI: 10.1016/j.bone.2015.10.019. View

13.

Mishima H, Sugaya H, Yoshioka T, Wada H, Aoto K, Hyodo K . 2. The Effect of Combined Therapy, Percutaneous Autologous Concentrated Bone Marrow Grafting and Low-Intensity Pulsed Ultrasound (LIPUS), on the Treatment of Non-Unions. J Orthop Trauma. 2016; 30(8):S2. DOI: 10.1097/01.bot.0000489987.43355.1d. View

14.

Peterson J, Okagbare P, de la Rosa S, Cilwa K, Perosky J, Eboda O . Early detection of burn induced heterotopic ossification using transcutaneous Raman spectroscopy. Bone. 2013; 54(1):28-34. PMC: 3690323. DOI: 10.1016/j.bone.2013.01.002. View

15.

Danielson P, Alfredson H, Forsgren S . Distribution of general (PGP 9.5) and sensory (substance P/CGRP) innervations in the human patellar tendon. Knee Surg Sports Traumatol Arthrosc. 2005; 14(2):125-32. DOI: 10.1007/s00167-005-0636-7. View

16.

Lu H, Hu J, Qin L, Chan K, Li G, Li K . Area, length and mineralization content of new bone at bone-tendon junction predict its repair quality. J Orthop Res. 2011; 29(5):672-7. DOI: 10.1002/jor.21292. View

17.

Niedzwiedzki T, Filipowska J . Bone remodeling in the context of cellular and systemic regulation: the role of osteocytes and the nervous system. J Mol Endocrinol. 2015; 55(2):R23-36. DOI: 10.1530/JME-15-0067. View

18.

Grassel S . The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology. Arthritis Res Ther. 2015; 16(6):485. PMC: 4395972. DOI: 10.1186/s13075-014-0485-1. View

19.

Chen J, Liu W, Zhao J, Sun C, Chen J, Hu K . Gelatin microspheres containing calcitonin gene-related peptide or substance P repair bone defects in osteoporotic rabbits. Biotechnol Lett. 2016; 39(3):465-472. DOI: 10.1007/s10529-016-2263-4. View

20.

Hu J, Qu J, Xu D, Zhang T, Qin L, Lu H . Combined application of low-intensity pulsed ultrasound and functional electrical stimulation accelerates bone-tendon junction healing in a rabbit model. J Orthop Res. 2013; 32(2):204-9. DOI: 10.1002/jor.22505. View