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RRP12 knockdown inhibited inflammation and p53/NF-κB pathway and alleviated heterotopic ossification in mice

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Published: 7 October 2026
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Heterotopic ossification (HO) is a pathological process, featured by the aberrant mature bone tissue in soft tissues outside the normal skeletal system, commonly occurring following trauma or major joint surgery. Ribosomal RNA Processing 12 Homolog (RRP12) has been confirmed to display multiple roles in ribosome synthesis, DNA damage, cell cycle and cell differentiation processes. However, the regulatory influences of RRP12 in HO progression keep vague and require further investigation. In this project, it was illustrated that RRP12 expression was markedly up-regulated in HO mice. Inhibition of RRP12 retarded the progression of HO in mice. Furthermore, RRP12 knockdown alleviated inflammation. Besides, it was revealed that suppression of RRP12 inactivated the p53/NF-κB pathway. Lastly, in bone marrow mesenchymal stem cells (BMSCs), it was verified that knockdown of RRP12 suppressed osteogenic differentiation of BMSCs. In conclusion, RRP12 knockdown inhibited inflammation and p53/NF-κB pathway and alleviated HO in mice. This study not only expands the current understanding of the molecular underpinnings of HO but also identifies RRP12 as a potential actionable target for therapeutic intervention. Nonetheless, further investigations are warranted to delineate the upstream regulators of RRP12 and to evaluate its translational feasibility in clinical settings.

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1. Pape HC, Marsh S, Morley JR, Krettek C, Giannoudis PV. Current concepts in the development of heterotopic ossification. J Bone Joint Surg Br 2004;86:783-7.
2. Bei M, Cao Q, Zhao C, Xiao Y, Chen Y, Xiao H, et al. Heterotopic ossification: Current developments and emerging potential therapies. Chin Med J (Engl) 2025;138:389-404.
3. Markes AR, Venishetty N, Gatto A, Swarup I. Pediatric heterotopic ossification: a comprehensive review. Curr Rev Musculoskelet Med 2023;16:514-20.
4. Cao G, Zhang S, Wang Y, Quan S, Yue C, Yao J, et al. Pathogenesis of acquired heterotopic ossification: Risk factors, cellular mechanisms, and therapeutic implications. Bone 2023;168:116655.
5. Prasad N, Ali A, Stanley D. Total elbow arthroplasty for non-rheumatoid patients with a fracture of the distal humerus: a minimum ten-year follow-up. Bone Joint J 2016;98-B:381-6.
6. Hongwei M, Tiebing Q, Zhiguo L, Kemin L. Proteomics study on biomarkers for heterotopic ossification secondary to traumatic brain injuries. J Rehabil Med 2020;52:jrm00001.
7. Edsberg LE, Crowgey EL, Osborn PM, Wyffels JT. A survey of proteomic biomarkers for heterotopic ossification in blood serum. J Orthop Surg Res 2017;12:69.
8. Moriggi G, Nieto B, Dosil M. Rrp12 and the Exportin Crm1 participate in late assembly events in the nucleolus during 40S ribosomal subunit biogenesis. PLoS Genet 2014;10:e1004836.
9. Dosil M. Ribosome synthesis-unrelated functions of the preribosomal factor Rrp12 in cell cycle progression and the DNA damage response. Mol Cell Biol 2011;31:2422-38.
10. An G, Liu Y, Hou Y, Lei Y, Bai J, He L, et al. RRP12 suppresses cell migration and invasion in colorectal cancer cell via regulation of epithelial-mesenchymal transition. J Gastrointest Oncol 2023;14:2111-23.
11. Lawand J, Loeffelholz Z, Khurshid B, Barcak E. Heterotopic ossification after trauma. Orthop Clin North Am 2023;54:37-46.
12. Monfrini E, Rinchetti P, Anheim M, Klingseisen A, Lagha-Boukbiza O, Cen Z, et al. RRP12 Variants are associated with autosomal recessive brain calcifications. Mov Disord 2025;40:2792-803.
13. Zhao Y, Liu F, Pei Y, Lian F, Lin H. Involvement of the Wnt/β-catenin signalling pathway in heterotopic ossification and ossification-related diseases. J Cell Mol Med 2024;28:e70113.
14. Choi YJ, Lee HW, Lee YS, Shim da M, Seo SW. RRP12 is a crucial nucleolar protein that regulates p53 activity in osteosarcoma cells. Tumour Biol 2016;37:4351-8.
15. Liu F, Zhao Y, Pei Y, Lian F, Lin H. Role of the NF-kB signalling pathway in heterotopic ossification: biological and therapeutic significance. Cell Commun Signal 2024;22:159.
16. Carrà G, Lingua MF, Maffeo B, Taulli R, Morotti A. P53 vs NF-κB: the role of nuclear factor-kappa B in the regulation of p53 activity and vice versa. Cell Mol Life Sci 2020;77:4449-58.
17. Tanaka T, Nakano T, Hozumi Y, Martelli AM, Goto K. Regulation of p53 and NF-κB transactivation activities by DGKζ in catalytic activity-dependent and -independent manners. Biochim Biophys Acta Mol Cell Res 2021;1868:118953.
18. Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in fibrodysplasia ossificans progressiva and other forms of heterotopic ossification. Curr Osteoporos Rep 2019;17:387-94.
19. Ren Y, Zhao W, Liu M, Lin H. Macrophage polarization in heterotopic ossification: inflammation, osteogenesis, and emerging therapeutic targets. Int J Mol Sci 2025;26:5821.
20. Chen Z, Xu Y, Qu C, Luo G, Cai Z, Liu H, et al. The IL-33/ST2 axis promotes traumatic heterotopic ossification by driving macrophage and mast cell-mediated inflammation via autophagy defects. Int J Biol Sci 2026;2260-85.
21. Chu W, Peng W, Wu Z, Xiong Y, Gao Z, Li Y, et al. PRMT6 is required for initiating and amplifying macrophage-induced inflammation in heterotopic ossification by increasing CCL2 expression. Bone Res 2026;14:29.
22. Li J, Sun Z, Luo G, Wang S, Cui H, Yao Z, et al. Quercetin Attenuates trauma-induced heterotopic ossification by tuning immune cell infiltration and related inflammatory insult. Front Immunol 2021;12:649285.
23. Rowe CJ, Nwaolu U, Salinas D, Hong J, Nunez J, Lansford JL, et al. Inhibition of focal adhesion kinase 2 results in a macrophage polarization shift to M2 which attenuates local and systemic inflammation and reduces heterotopic ossification after polysystem extremity trauma. Front Immunol 2023;14:1280884.
24. Cholok D, Chung MT, Ranganathan K, Ucer S, Day D, Davis TA, et al. Heterotopic ossification and the elucidation of pathologic differentiation. Bone 2018;109:12-21.
25. Ju J, Yu D, Xue F, Zhao Y, Shi W, Pan M, et al. Inhibition of Nf-ҝb prevents trauma-induced heterotopic ossification in rat model. Connect Tissue Res 2019;60:304-10.
26. Huang J, Wu J, Lin J, Li C, Tang B, Xiao H. Palovarotene inhibits the NF-κB signalling pathway to prevent heterotopic ossification. Clin Exp Pharmacol Physiol 2022;49:881-92.
27. Wang H, Song D, Wei L, Huang L, Wei D, Su Y, et al. Ethyl caffeate inhibits macrophage polarization via SIRT1/NF-κB to attenuate traumatic heterotopic ossification in mice. Biomed Pharmacother 2023;161:114508.
28. Hou J, Chen J, Fan J, Tang Z, Zhou W, Lin H. Inhibition of NF-κB signaling-mediated crosstalk between macrophages and preosteoblasts by metformin alleviates trauma-induced heterotopic ossification. Inflammation 2023;46:1414-29.
29. Lowe JM, Menendez D, Bushel PR, Shatz M, Kirk EL, Troester MA, et al. p53 and NF-κB coregulate proinflammatory gene responses in human macrophages. Cancer Res 2014;74:2182-92.
30. Ramirez DM, Ramirez MR, Reginato AM, Medici D. Molecular and cellular mechanisms of heterotopic ossification. Histol Histopathol 2014;29:1281-5.
31. Shu LZ, Zhang XL, Ding YD, Lin H. From inflammation to bone formation: the intricate role of neutrophils in skeletal muscle injury and traumatic heterotopic ossification. Exp Mol Med 2024;56:1523-30.

Ethics Approval

The animal experiments were approved by the Ethics Committee of Lu'an People’s Hospital

CRediT authorship contribution

Yuchen Hu, conceptualization, methodology, investigation, writing – original draft, writing – review & editing. Zihao Zeng, conceptualization, methodology, investigation, writing – original draft, writing – review & editing. Wen Jin, conceptualization, methodology, investigation, writing – original draft, writing – review & editing. Chenggang Wang, supervision, data curation, formal analysis. Xiaofeng Liu, formal analysis. Yusheng Sun, validation. Qing Gao, validation. 

Supporting Agencies

Science and Technology Project of Bengbu Medical University

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

How to Cite



1.
Hu Y, Zeng Z, Jin W, Wang C, Liu X, Sun Y, et al. RRP12 knockdown inhibited inflammation and p53/NF-κB pathway and alleviated heterotopic ossification in mice. Eur J Histochem [Internet]. 2026 Oct. 7 [cited 2026 Oct. 7];70(4). Available from: https://www.ejh.it/ejh/article/view/4730