Kidney Week

Abstract: SA-PO0287

SERPINA3N: Mediator of Osteogenic Dysfunction in CKD-Associated Iron Deficiency

Session Information

• Bone and Mineral Metabolism: Basic Research
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Kirschner, Katharina M., Indiana University School of Medicine, Indianapolis, Indiana, United States

Katharina M. Kirschner

• Edwards, Daniel Fullerton, Eastern Michigan University, Ypsilanti, Michigan, United States

Daniel Fullerton Edwards

• Matz, Jordan Ashley, Indiana University School of Medicine, Indianapolis, Indiana, United States

Jordan Ashley Matz, MS

• Toubin, Max, Indiana University School of Medicine, Indianapolis, Indiana, United States

Max Toubin

• Segvich, Dyann, Purdue University, Indianapolis, Indiana, United States

Dyann Segvich

• Wallace, Joseph M., Purdue University, Indianapolis, Indiana, United States

Joseph M. Wallace, PhD

• Pelletier, Stephane, Indiana University School of Medicine, Indianapolis, Indiana, United States

Stephane Pelletier, MSc, PhD

• Clinkenbeard, Erica, Indiana University School of Medicine, Indianapolis, Indiana, United States

Erica Clinkenbeard, PhD

Background

Chronic kidney disease (CKD) disrupts skeletal homeostasis, driving mineral and bone disorders (CKD-MBD) and elevating fracture risk. Iron deficiency, a common CKD comorbidity, exacerbates osteoblast (OB) dysfunction and impairs mineralization, yet the molecular mechanisms remain unclear. The serine protease inhibitor SERPINA3N is upregulated in iron-deficient conditions and linked to reduced OB activity in vitro, but its role in CKD-associated bone pathology is unknown. Here, we combined iron chelation in MPC2-derived OBs, an adenine-diet CKD murine model, and a novel global Serpina3-knockout to investigate SERPINA3N’s contribution to skeletal complications in CKD and its therapeutic potential.

Methods

Bulk RNA-seq was run on MPC2 cells differentiated in osteogenic media and treated with deferoxamine (DFO; iron chelator). mRNA/protein validation used qPCR and immunoblotting. For in vivo studies, C57Bl/6 mice received a 6-week 0.2% adenine diet to model CKD, with Serpina3n/SERPINA3N assessed in bone and plasma. Humans encode one SERPINA3 gene; mice have 14 Serpina3 paralogs. Global Serpina3-knockout mice, lacking the entire Serpina3 locus for translational relevance (SerpinA3^LD), were generated to evaluate bone development and therapeutic relevance.

Results

RNA-seq of DFO-treated OBs revealed broad transcriptomic changes, with persistent downregulation of osteogenic genes (Bglap, Col1a1, Alpl, Dmp1) and robust, dose-dependent upregulation of Serpina3n (2.639 log₂FC; p-adj 0.00012). In vivo, CKD mice developed iron deficiency, marked by elevated hepcidin, reduced serum iron, and reduced OB function. Accordingly, Serpina3n levels surged in CKD tibiae versus controls (male p=0.0074; female p=0.0002), with cortical bone lysate showing SERPINA3N protein accumulation, while plasma levels were unchanged. This bone-specific overexpression links SERPINA3N to CKD-driven iron deficiency and OB dysfunction, implicating it in bone pathology in CKD. Analysis of 8-week-old SerpinA3^LD mice had no significant bone abnormalities or changes in osteogenic markers, suggesting Serpina3 loss does not impair bone anatomy.

Conclusion

SERPINA3N is identified as a novel mediator of impaired bone mineralization in CKD and may represent a new therapeutic target to improve skeletal outcomes in this population.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025abrbm0z1