GDF15 contributes to inflammasome-associated excessive mechanoresponses of hyperlipidemic PdL fibroblasts
- 1Department of Orthodontics, Jena University Hospital, Jena Germany
Abstract
Orthodontic tooth movement relies on a tightly regulated pro-inflammatory and pro resorptive mechanoresponse of local periodontal ligament fibroblasts (PdLFs). Dysregulation is linked to complications such as root resorption and tooth loss. Hyperlipidemic conditions promote excessive PdL mechanoresponses, with growth differentiation factor 15 (GDF15) acting as potential regulator. This study examined the contribution of the inflammasome/pyroptosis pathway as underlying mechanism for dysregulated mechanoresponses. Human PdLFs were treated with palmitic acid (PA) or oleic acid (OA) for six days before 24 hours of compressive loading. PA increased CASP1, CASP4, and CASP3 activity, secretion of IL-1{beta}, IL-18, and HMGB1, and LDH release. Pharmacological blockade and siRNA-mediated knockdown of inflammasome- and pyroptosis-related targets revealed that NLRP3, CASP1, CASP4, and GSDMD partially contributed to monocyte and osteoclast overactivation. Silencing PA-increased GDF15, partially normalized the phenotype, at least in part by inflammasome/pyroptosis regulation. GDF15 acted through extracellular, and a nuclear signaling route, each accounting partially to this phenotype. Together, GDF15 partially regulates the PA-induced, pyroptosis-associated overactivated mechanoresponse alongside pyroptosis-independent mechanisms suggesting it as an interesting target for potential clinical interventions.
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BibTeX
@misc{baumbach2026gdf15,
title = {{GDF15 contributes to inflammasome-associated excessive mechanoresponses of hyperlipidemic PdL fibroblasts}},
author = {M. Baumbach and A. Manzolillo and F. Ghazvini Zadegan and R. Yeskendirova and A. Doeding and C.-L. Hennig and U. Schulze-Spaete and J. Symmank and C. Jacobs},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.30.748125},
url = {https://www.biorxiv.org/content/10.64898/2026.08.30.748125v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - GDF15 contributes to inflammasome-associated excessive mechanoresponses of hyperlipidemic PdL fibroblasts
AU - M. Baumbach
AU - A. Manzolillo
AU - F. Ghazvini Zadegan
AU - R. Yeskendirova
AU - A. Doeding
AU - C.-L. Hennig
AU - U. Schulze-Spaete
AU - J. Symmank
AU - C. Jacobs
PY - 2026
DA - 2026/08/30
PB - bioRxiv
DO - 10.64898/2026.08.30.748125
UR - https://www.biorxiv.org/content/10.64898/2026.08.30.748125v1
AB - Orthodontic tooth movement relies on a tightly regulated pro-inflammatory and pro resorptive mechanoresponse of local periodontal ligament fibroblasts (PdLFs). Dysregulation is linked to complications such as root resorption and tooth loss. Hyperlipidemic conditions promote excessive PdL mechanoresponses, with growth differentiation factor 15 (GDF15) acting as potential regulator. This study examined the contribution of the inflammasome/pyroptosis pathway as underlying mechanism for dysregulated mechanoresponses. Human PdLFs were treated with palmitic acid (PA) or oleic acid (OA) for six days before 24 hours of compressive loading. PA increased CASP1, CASP4, and CASP3 activity, secretion of IL-1{beta}, IL-18, and HMGB1, and LDH release. Pharmacological blockade and siRNA-mediated knockdown of inflammasome- and pyroptosis-related targets revealed that NLRP3, CASP1, CASP4, and GSDMD partially contributed to monocyte and osteoclast overactivation. Silencing PA-increased GDF15, partially normalized the phenotype, at least in part by inflammasome/pyroptosis regulation. GDF15 acted through extracellular, and a nuclear signaling route, each accounting partially to this phenotype. Together, GDF15 partially regulates the PA-induced, pyroptosis-associated overactivated mechanoresponse alongside pyroptosis-independent mechanisms suggesting it as an interesting target for potential clinical interventions.
ER -