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Sexual Dimorphism in Ligature-Induced Periodontitis Is Mediated by the miR-141-200c Cluster - Chawin Upara3.16 MB
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Dissertation
Sexual dimorphism in ligature-induced periodontitis is mediated by the miR-141/200c cluster
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008384
Abstract
Periodontitis is a chronic inflammatory disease characterized by destruction of the tooth-supporting tissues and is strongly influenced by host immune responses. Epidemiological studies demonstrate sexual dimorphism in periodontitis, but the molecular mechanisms responsible for sex-specific differences in disease severity remain unclear. MicroRNAs regulate inflammatory signaling, bone metabolism, and host-microbe interactions, making them potential upstream modulators of periodontal susceptibility. MiR-141 and miR-200c have been implicated in immune regulation and bone biology, as well as periodontitis. These two microRNAs have also been reported to have a sex-biased expression during rodent cortical development and in the physiological brain and after stroke, but its role in sex-dependent periodontal disease has not been defined. The objective of this study was to determine whether the miR-141/200c cluster regulates sexual dimorphism in ligature-induced periodontitis and to identify the biological mechanisms involved. Understanding miRNA-mediated regulation of sex-specific immune responses in the context of periodontitis will contribute to the development of personalized therapeutic strategies for periodontal disease and other chronic inflammatory conditions.
Ligature-induced periodontitis was performed in male and female wild-type (WT) and the miR-141/200c cluster knockout (KO) mice. Alveolar bone loss was quantified using micro-computed tomography (micro-CT). Oral microbiome composition was analyzed using 16S rRNA sequencing. Bone quality was assessed by micro-CT, systemic inflammatory mediators were measured using protein arrays, and gingival transcriptome profiling was performed using RNA-sequencing followed by gene set enrichment analysis.
Early ligature-induced periodontitis produced greater alveolar bone loss in WT females than males. Under physiological conditions, WT females showed a trend towards higher gingival miR-200c expression than males while miR-141 remained identical. We then demonstrated that after knocking out the miR-141/200c cluster, KO females had a significantly lower severity of periodontitis compared to WT females, and were the same as males, thus abolishing sexual dimorphism.
Deletion of the miR-141/200c cluster altered oral microbiome composition in females, eliminating the distinct microbial profile observed in WT female. The baseline bone mineral density and microarchitecture were investigated, and no differences were found comparing KO to WT mice of the same sex, suggesting that bone quality remained unchanged. KO mice displayed altered systemic inflammatory mediator profiles, indicating that the miR-141/200c cluster influences baseline immune regulation in both males and females, and specifically a reduction in circulating TNF RII, IL-12 p40/p70, and MIP-1γ in ligated KO females.
Gingival transcriptome analysis revealed that deletion of the cluster significantly suppressed multiple inflammatory pathways in females during periodontitis, including TNF, IL-17, NF-κB, chemokine, and osteoclast differentiation signaling. Estrogen signaling pathway was also increased in periodontitis of KO females without changes in circulating estradiol, suggesting post-receptor regulation. Additionally, the X-linked anti-inflammatory gene Ace2, which is also a direct target of miR-200c, was upregulated in ligated KO females, supporting a role for sex-dependent gene regulation.
These findings demonstrate that the miR-141/200c cluster is a key regulator of sexual dimorphism in periodontitis. The cluster influences disease severity through coordinated modulation of inflammatory signaling, host-microbiome interactions, and gene expression in a sex-dependent manner rather than through intrinsic bone differences.
Details
- Title: Subtitle
- Sexual dimorphism in ligature-induced periodontitis is mediated by the miR-141/200c cluster
- Creators
- Chawin Upara
- Contributors
- Liu Hong (Advisor)Huojun Cao (Committee Member)Jeffrey A. Banas (Committee Member)Ling Yang (Committee Member)Sukirth M. Ganesan (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Oral Science
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008384
- Publisher
- University of Iowa
- Number of pages
- xvi, 99 pages
- Copyright
- Copyright 2026 Chawin Upara
- Language
- English
- Date submitted
- 04/23/2026
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 68-87).
- Public Abstract (ETD)
Periodontitis is a common disease that damages the gums and bone supporting the teeth and is a major cause of tooth loss. The disease develops when the body reacts too strongly to oral bacteria. It has been established that men develop periodontitis more commonly and with greater severity than women, but the biological reasons underlying these differences remain incompletely understood.
MicroRNAs are small molecules in the body that influence how genes are translated into proteins and can affect inflammation, bone biology, and immune responses. This study focused on a pair of microRNAs, miR-141 and miR-200c, to determine whether they affect how males and females respond differently to periodontal disease.
Using a mouse model of periodontitis, we compared normal mice with mice lacking the miR-141/200c gene cluster. Female mice normally developed more severe disease during the early stage, but this difference disappeared when the microRNA cluster was deleted. This shift was associated with differences in inflammatory responses, oral bacterial ecology, and gene activity in the gum tissue, rather than changes in baseline bone parameters. We also found that these microRNAs affect several immune signaling pathways and interact with sex hormone-related processes and a gene that is produced from the X chromosome that differ between males and females.
These results show that the miR-141/200c cluster helps control how the body responds to periodontal disease in a sex-dependent manner. Understanding these mechanisms may support more personalized prevention and treatment strategies that incorporate biological sex into periodontal care.
- Academic Unit
- Oral Pathology, Radiology and Medicine
- Record Identifier
- 9985176974702771
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