2. Academic Validation
  3. Endoplasmic reticulum stress and autophagy as potential therapeutic targets in SERPINF1 mutation-induced type VI osteogenesis imperfecta

Endoplasmic reticulum stress and autophagy as potential therapeutic targets in SERPINF1 mutation-induced type VI osteogenesis imperfecta

  • Life Sci. 2025 Jul 19:379:123862. doi: 10.1016/j.lfs.2025.123862.
Yang Tian 1,  Xinyu Chen 1,  Shuoshuo Wei 2,  Wanhong Wu 1,  Luna Liu 1,  Yingzhou Shi 1,  Huixiao Wu 1,  Zongyue Li 1,  Jie Jiang 3,  Wanyi Zhao 1,  Yanzhou Wang 4,  Tianyou Li 4,  Yangyang Yao 4,  Jiajun Zhao 1,  Chao Xu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; "Chuangxin China" Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China.
  • 2 Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, China; Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, China.
  • 3 Department of Neonatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong, China.
  • 4 Department of Pediatric Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong, China.
  • 5 Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; "Chuangxin China" Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China; Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong 250021, China. Electronic address: doctorxuchao@163.com.
PMID: 40692043 DOI: 10.1016/j.lfs.2025.123862
Abstract

Background: Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Mutations in the SERPINF1 gene are known to cause a rare, autosomal recessive form of type VI OI. The pathogenic mechanisms underlying type VI OI caused by mutations in the SERPINF1 gene remain unclear.

Methods: Clinical data and genetic analysis were obtained from two unrelated families with type VI OI. Functional studies were performed in MC3T3-E1 osteoblast cells transfected with mutant pigment epithelium-derived factor (PEDF) plasmids. Subsequently, the pathogenesis of novel mutations was investigated through analyses of protein expression, subcellular localization, cell Apoptosis, endoplasmic reticulum (ER) stress, and degradation pathways.

Results: Three novel mutations in the SERPINF1 gene were identified in two patients with type VI OI. Subsequent validation in MC3T3-E1 cells demonstrated that all three mutant PEDF proteins failed to be properly secreted and instead accumulated abnormally in the ER. Further analysis indicated that mutant PEDF proteins impaired osteoblast differentiation and mineralization, promoted Apoptosis, and induced ER stress. Additionally, mutant PEDF protein-induced ER stress was found to alleviate intracellular protein accumulation through ER-associated degradation (ERAD) and Autophagy.

Conclusion: This study identifies three novel mutations in the SERPINF1 gene associated with type VI OI, which disrupt PEDF protein secretion and lead to its accumulation in osteoblasts, causing cell Apoptosis and ER stress. Cells attempt to mitigate this stress through ERAD and Autophagy. These findings reveal a novel pathogenic mechanism in type VI OI and highlight the role of ER stress and Autophagy.

Keywords

Apoptosis; Autophagy; Endoplasmic reticulum stress; Osteogenesis imperfecta; PEDF; SERPINF1.

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