Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formation
Objective: Heterotopic ossification (HO) refers to the abnormal development of bone in soft tissue rather than within bone itself. Previous research has shown that sensory nerve prostaglandin E2 receptor 4 (EP4) signaling not only governs pain perception but also influences bone formation. However,...
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Elsevier
2024-11-01
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| Series: | Journal of Orthopaedic Translation |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214031X24001219 |
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| author | Rongmin Lin Hancheng Lin Chencheng Zhu Jieming Zeng Jiahui Hou Ting Xu Yihui Tan Xuyou Zhou Yuan Ma Mankai Yang Kuanhai Wei Bin Yu Hangtian Wu Zhuang Cui |
| author_facet | Rongmin Lin Hancheng Lin Chencheng Zhu Jieming Zeng Jiahui Hou Ting Xu Yihui Tan Xuyou Zhou Yuan Ma Mankai Yang Kuanhai Wei Bin Yu Hangtian Wu Zhuang Cui |
| author_sort | Rongmin Lin |
| collection | DOAJ |
| description | Objective: Heterotopic ossification (HO) refers to the abnormal development of bone in soft tissue rather than within bone itself. Previous research has shown that sensory nerve prostaglandin E2 receptor 4 (EP4) signaling not only governs pain perception but also influences bone formation. However, the relationship between sensory nerve EP4 and the pathogenesis of HO in the Achilles tendon remains unclear. This study aims to investigate this relationship and the underlying mechanisms. Methods: We generated sensory nerve EP4-specific knockout mice, with the genotype of Avil-CreEP4fl/fl, was propagated. Transcriptome sequencing and bioinformatics analysis techniques were used to identify the potential molecular pathways involving with sensory nerve EP4. Additionally, a neurectomy mouse model was created by transecting the sciatic nerve transection, to examine the effects and mechanisms of peripheral innervation on HO in vivo. Micro-CT, immunofluorescence (IF), Hematoxylin and Eosin (H&E) Staining, Safranin O-Fast Green staining and western blotting were used to analyze changes in cellular and tissue components. Results: We here observed an increase in sensory nerve EP4 and H-type vessels during the pathogenesis of HO in both human subjects and mice. Proximal neurectomy through sciatic nerve transection or the targeted knockout of EP4 in sensory nerves hindered angiogenesis-dependent bone formation and the development of HO at the traumatic site of the Achilles tendon. Furthermore, we identified the Efnb2 (Ephrin-B2)/Dll4 (Delta-like ligand 4) axis as a potential downstream element influenced by sensory nerve EP4 in the regulation of HO. Notably, administration of an EP4 inhibitor demonstrated the ability to alleviate HO. Based on these findings, sensory nerve EP4 emerges as an innovative and promising approach for managing HO. Conclusion: Our findings demonstrate that the sensory nerve EP4 promotes ectopic bone formation by modulating angiogenesis-associated osteogenesis during HO. The translational potential of this article: Our results provide a mechanistic rationale for targeting sensory nerve EP4 as a promising candidate for HO therapy. |
| format | Article |
| id | doaj-art-d0df0bd56d8747e88da819b1dba43086 |
| institution | Kabale University |
| issn | 2214-031X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Orthopaedic Translation |
| spelling | doaj-art-d0df0bd56d8747e88da819b1dba430862024-12-05T05:20:27ZengElsevierJournal of Orthopaedic Translation2214-031X2024-11-0149325338Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formationRongmin Lin0Hancheng Lin1Chencheng Zhu2Jieming Zeng3Jiahui Hou4Ting Xu5Yihui Tan6Xuyou Zhou7Yuan Ma8Mankai Yang9Kuanhai Wei10Bin Yu11Hangtian Wu12Zhuang Cui13Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaDepartment of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaDepartment of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaGuangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou, Guangdong, 510515, ChinaDepartment of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaDepartment of Sleep Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaThe Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510130, ChinaDepartment of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaDepartment of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaDepartment of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaDepartment of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, ChinaDepartment of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China; Corresponding author. Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China; Corresponding author. Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Key laboratory of bone and cartilage regeneration medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China; Corresponding author. Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.Objective: Heterotopic ossification (HO) refers to the abnormal development of bone in soft tissue rather than within bone itself. Previous research has shown that sensory nerve prostaglandin E2 receptor 4 (EP4) signaling not only governs pain perception but also influences bone formation. However, the relationship between sensory nerve EP4 and the pathogenesis of HO in the Achilles tendon remains unclear. This study aims to investigate this relationship and the underlying mechanisms. Methods: We generated sensory nerve EP4-specific knockout mice, with the genotype of Avil-CreEP4fl/fl, was propagated. Transcriptome sequencing and bioinformatics analysis techniques were used to identify the potential molecular pathways involving with sensory nerve EP4. Additionally, a neurectomy mouse model was created by transecting the sciatic nerve transection, to examine the effects and mechanisms of peripheral innervation on HO in vivo. Micro-CT, immunofluorescence (IF), Hematoxylin and Eosin (H&E) Staining, Safranin O-Fast Green staining and western blotting were used to analyze changes in cellular and tissue components. Results: We here observed an increase in sensory nerve EP4 and H-type vessels during the pathogenesis of HO in both human subjects and mice. Proximal neurectomy through sciatic nerve transection or the targeted knockout of EP4 in sensory nerves hindered angiogenesis-dependent bone formation and the development of HO at the traumatic site of the Achilles tendon. Furthermore, we identified the Efnb2 (Ephrin-B2)/Dll4 (Delta-like ligand 4) axis as a potential downstream element influenced by sensory nerve EP4 in the regulation of HO. Notably, administration of an EP4 inhibitor demonstrated the ability to alleviate HO. Based on these findings, sensory nerve EP4 emerges as an innovative and promising approach for managing HO. Conclusion: Our findings demonstrate that the sensory nerve EP4 promotes ectopic bone formation by modulating angiogenesis-associated osteogenesis during HO. The translational potential of this article: Our results provide a mechanistic rationale for targeting sensory nerve EP4 as a promising candidate for HO therapy.http://www.sciencedirect.com/science/article/pii/S2214031X24001219AngiogenesisEfnb2EP4Heterotopic ossificationSensory nerve |
| spellingShingle | Rongmin Lin Hancheng Lin Chencheng Zhu Jieming Zeng Jiahui Hou Ting Xu Yihui Tan Xuyou Zhou Yuan Ma Mankai Yang Kuanhai Wei Bin Yu Hangtian Wu Zhuang Cui Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formation Journal of Orthopaedic Translation Angiogenesis Efnb2 EP4 Heterotopic ossification Sensory nerve |
| title | Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formation |
| title_full | Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formation |
| title_fullStr | Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formation |
| title_full_unstemmed | Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formation |
| title_short | Sensory nerve EP4 facilitates heterotopic ossification by regulating angiogenesis-coupled bone formation |
| title_sort | sensory nerve ep4 facilitates heterotopic ossification by regulating angiogenesis coupled bone formation |
| topic | Angiogenesis Efnb2 EP4 Heterotopic ossification Sensory nerve |
| url | http://www.sciencedirect.com/science/article/pii/S2214031X24001219 |
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