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Abnormal expression of Pappa2 gene may indirectly affect mouse hip development through the IGF signaling pathway
Yufan Chen1, Lianyong Li2, Enbo Wang1
1Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang City, 110004, Liaoning Province, PR China.
Insights
Pregnancy-associated plasma protein-A2 (PAPP-A2) influences hip development by affecting fibrous and cartilaginous metabolism. Downregulating PAPP-A2 reduces collagen synthesis and cartilage proliferation, impacting developmental dysplasia of the hip (DDH).
Area of Science:
- Developmental biology
- Genetics
- Orthopedics
Background:
- Developmental dysplasia of the hip (DDH) is a significant cause of childhood disability with unclear genetic mechanisms.
- Previous research identified a significant association between pregnancy-associated plasma protein-A2 (PAPP-A2) and DDH.
Purpose of the Study:
- To investigate the role of PAPP-A2 in DDH pathogenesis.
- To examine insulin-like growth factor (IGF) expression, collagen synthesis, and cartilage proliferation in response to altered PAPP-A2 levels.
Main Methods:
- In vivo: Lentivirus-mediated PAPP-A2 knockdown in mouse hips to assess protein expression and localization.
- In vitro: Cultured mouse fibroblasts and chondrocytes with PAPP-A2 manipulation and IGFBP-5 to evaluate protein and mRNA expression.
Main Results:
- PAPP-A2 knockdown in mice led to decreased cartilage proliferation proteins in the acetabulum and femoral head.
- IGF expression was downregulated in soft tissues around the acetabulum.
- In vitro, PAPP-A2 downregulation or IGFBP-5 upregulation reduced collagen synthesis and cartilage proliferation.
Conclusions:
- PAPP-A2 is implicated in mouse hip joint development.
- PAPP-A2 may interfere with fibrous and cartilaginous metabolism through IGF pathway-associated proteins.
- Findings suggest PAPP-A2 as a potential factor in DDH development.
Introduction:
Developmental dysplasia of the hip (DDH) is a major cause of disability in children, and the genetic mechanism of this disease remains unclear. In our previous study, we found that pregnancy-associated plasma protein-A2 (PAPP-A2) was associated with DDH significantly.
Objectives:
The aim of this study was to investigate the insulin-like growth factor (IGF) expression and collagen synthesis as well as cartilage proliferation-related proteins in the case of abnormal expression of Pappa2 in mice to research the relationship between PAPP-A2 and the pathological changes of DDH.
Methods:
In vivo animal experiments, the mice were directly injected with 50 µl of Cas9/PAPP-A2 sgRNA lentiviruses around the hip to downregulate the Pappa2 gene expression and injected with control lentiviruses on the other side, then to observe the expression and localization of related proteins. And in an in vitro experiment, mice fibroblasts and primary chondrocytes were cultured with insulin-like growth factor binding protein-5 (IGFBP-5) protein, PAPP-A2 protein and Cas9/PAPP-A2 sgRNA lentiviruses to detect of related proteins and mRNA expression.
Results:
Cartilage proliferation-related proteins demonstrated a significant decrease in the PAPP-A2 knockdown hips acetabulum and femoral head cartilage, meanwhile the IGF expression was also downregulated in the soft tissue around the acetabulum compared with the control hips. Furthermore, the role PAPP-A2 played in chondrocytes and fibroblasts was the same as in the in vivo experiments, downregulation of PAPP-A2 expression or upregulation of IGFBP-5 expression can reduce collagen synthesis and cartilage proliferation.
Conclusions:
PAPP-A2 may be involved in the development of the mouse hip joint by interfering the fibrous and cartilaginous metabolism via IGF pathway-associated proteins pathway.
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