Today is October 20th, World Osteoporosis Day. When mentioning osteoporosis, many people think of fractures in the elderly caused by calcium deficiency. However, there is a rare disease where patients face the challenge of extremely fragile bones from birth - Osteogenesis Imperfecta (OI), also known as brittle bone disease.
 

What is Osteogenesis Imperfecta (OI)?
 

Osteogenesis Imperfecta is a hereditary connective tissue disorder that primarily affects bone strength and density, with an incidence of 1 in 5,000. Patients typically present with brittle fractures, short stature, and skeletal deformities. They may also exhibit connective tissue abnormalities such as joint ligament laxity, blue or gray sclera, dentinogenesis imperfecta, and hearing impairment. Frequent brittle fractures, low bone density, and positive family history are the most important clinical features.

The homeostasis of the human skeletal system relies on the dynamic balance between osteoblasts and osteoclasts, responsible for bone formation and resorption, respectively. In OI patients, osteoblast function is impaired, affecting collagen synthesis, secretion, and mineralization processes, leading to bone fragility.
 

I. Pathogenesis

Based on clinical manifestations and genetic characteristics, OI can be classified into several subtypes:
 

Type I: Incidence approximately 40%, caused by mutations in the COL1A1 gene encoding the α1 chain of type I collagen, leading to premature termination codons and reduced synthesis of functional type I collagen.
 

 

Image source: PubMed

Types II and IV: Incidence approximately 10% and 20%, respectively, caused by single base mutations in the α1 chain of type I collagen, resulting in glycine (Gly) replacement by other amino acids, affecting the triple helix structure and causing phenotypes of varying severity.
 

Type III: Incidence approximately 30%, caused by point mutations in COL1A1 or COL1A2 genes, and may also involve mutations in other genes affecting collagen synthesis and processing, such as CRTAP, P3H1 (LEPRE1), PPIB (CYPB), etc. These mutations may affect collagen modification, processing, and cross-linking, further impacting bone strength and stability.
 

Gene Therapy
 

Gene Replacement Therapy: Using adeno-associated virus (AAV) vectors to deliver normal COL1A1 or COL1A2 genes into patients to restore normal type I collagen expression.

Gene Silencing Technology: Utilizing small interfering RNA (siRNA) or antisense oligonucleotide (ASO) technology to specifically silence mutant COL1A1 or COL1A2 genes, reducing abnormal protein production.

Signal Regulation: Inhibiting the TGF-β signaling pathway to alleviate the progression of bone lesions.
 

Mouse Models
 

oim/oim mice: Type I, Col1a2 gene deletion, characterized by high bone fragility, low bone mass, long bone fractures, and skeletal deformities.

Brtl/Col1a1G349C mice: Type IV, Col1a1 gene Gly→Cys point mutation, bone strength reduced by approximately 50%, may present with blue sclera.

Crtap⁻/⁻ mice: Type VII, collagen prolyl 3-hydroxylase complex component deficiency, leading to excessive collagen modification and severe bone dysplasia.

FKBP10⁻/⁻ mice: Type IX, collagen folding chaperone deficiency, long bone bending, dentin abnormalities, suitable for cross-correction studies.

PPIB⁻/⁻ mice: Type X, peptidyl-prolyl cis-trans isomerase B deficiency, affecting collagen folding, accompanied by cardiovascular phenotypes such as aortic aneurysm.

Jrt/Col1a1G610C mice: Col1a1 gene Gly610Cys point mutation, progressive bone loss, multiple fractures.
 

MingCeler Biotech's Tetraploid Complementation Technology
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.

MingCeler Biotech can customize various Osteogenesis Imperfecta (OI) mouse models according to client needs, such as oim/oim mice, Brtl/Col1a1G349C mice, Crtap⁻/⁻ mice, FKBP10⁻/⁻ mice, PPIB⁻/⁻ mice, and Jrt/Col1a1G610C mice. We welcome inquiries!
 

References:

[1]https://csobmr.cma.org.cn/ncontent.aspx?oid=540

[2]Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. 2016 Apr 16;387(10028):1657-71. doi: 10.1016/S0140-6736(15)00728-X. Epub 2015 Nov 3. PMID: 26542481; PMCID: PMC7384887.

[3]Etich J, Leßmeier L, Rehberg M, Sill H, Zaucke F, Netzer C, Semler O. Osteogenesis imperfecta-pathophysiology and therapeutic options. Mol Cell Pediatr. 2020 Aug 14;7(1):9. doi: 10.1186/s40348-020-00101-9. PMID: 32797291; PMCID: PMC7427672.

Special Statement:This article is sourced from the official website of MingCeler Biotech. Personal sharing is permitted. However, media outlets or organizations are strictly prohibited from reprinting or republishing this content on any other platform without prior authorization. For reprint authorization or other cooperation inquiries, please contact: sales@mingceler.com.

Disclaimer: Some materials used are sourced from the internet. If any infringement occurs, please contact us for removal. This article is intended for informational purposes only and does not constitute medical advice or provide treatment recommendations. The views expressed herein do not represent the official stance of MingCeler Biotech, nor do they imply Mingceler Biotech's endorsement or opposition to the opinions presented.