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The p27 Pathway Modulates the Regulation of Skeletal Growth and Osteoblastic Bone Formation by Parathyroid
Min Zhu1, Jing Zhang2, Zhan Dong1
1State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, People's Republic of China.
Abstract:
Parathyroid hormone-related peptide (PTHrP) 1-84 knock-in mice (Pthrp KI) develop skeletal growth retardation and defective osteoblastic bone formation. To further examine the mechanisms underlying this phenotype, microarray analyses of differential gene expression profiles were performed in long bone extracts from Pthrp KI mice and their wild-type (WT) littermates. We found that the expression levels of p27, p16, and p53 were significantly upregulated in Pthrp KI mice relative to WT littermates. To determine whether p27 was involved in the regulation by PTHrP of skeletal growth and development in vivo, we generated compound mutant mice, which were homozygous for both p27 deletion and the Pthrp KI mutation (p27(-/-) Pthrp KI). We then compared p27(-/-) Pthrp KI mice with p27(-/-), Pthrp KI, and WT littermates. Deletion of p27 in Pthrp KI mice resulted in a longer lifespan, increased body weight, and improvement in skeletal growth. At 2 weeks of age, skeletal parameters, including length of long bones, size of epiphyses, numbers of proliferating cell nuclear antigen (PCNA)-positive chondrocytes, bone mineral density, trabecular bone volume, osteoblast numbers, and alkaline phosphatase (ALP)-, type I collagen-, and osteocalcin-positive bone areas were increased in p27(-/-) mice and reduced in both Pthrp KI and p27(-/-) Pthrp KI mice compared with WT mice; however, these parameters were increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. As well, protein expression levels of PTHR, IGF-1, and Bmi-1, and the numbers of total colony-forming unit fibroblastic (CFU-f) and ALP-positive CFU-f were similarly increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. Our results demonstrate that deletion of p27 in Pthrp KI mice can partially rescue defects in skeletal growth and osteoblastic bone formation by enhancing endochondral bone formation and osteogenesis. These studies, therefore, indicate that the p27 pathway may function downstream in the action of PTHrP to regulate skeletal growth and development.
Insights
Parathyroid hormone-related peptide (PTHrP) knock-in mice show skeletal growth defects. Deleting p27 in these mice partially rescues growth and bone formation by enhancing endochondral bone development.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Parathyroid hormone-related peptide (PTHrP) plays a crucial role in skeletal development.
- PTHrP knock-in (Pthrp KI) mice exhibit skeletal growth retardation and impaired osteoblastic bone formation.
- Gene expression analysis revealed upregulation of p27, p16, and p53 in Pthrp KI mice.
Purpose of the Study:
- To investigate the role of p27 in PTHrP-mediated regulation of skeletal growth and development.
- To determine if p27 deletion can ameliorate the skeletal defects observed in Pthrp KI mice.
Main Methods:
- Generated compound mutant mice (p27(-/-) Pthrp KI) by crossing p27 knockout mice with Pthrp KI mice.
- Compared skeletal parameters, bone formation markers, and protein expression in p27(-/-) Pthrp KI mice with p27(-/-), Pthrp KI, and wild-type (WT) littermates.
- Utilized microarray analysis to assess gene expression profiles in long bone extracts.
Main Results:
- Deletion of p27 in Pthrp KI mice (p27(-/-) Pthrp KI) led to increased lifespan, body weight, and improved skeletal growth compared to Pthrp KI mice.
- Skeletal parameters, including long bone length, epiphyseal size, chondrocyte proliferation (PCNA+), bone mineral density, and osteoblast markers (ALP+, collagen I+, osteocalcin+), were partially restored in p27(-/-) Pthrp KI mice.
- Protein levels of PTHR, IGF-1, Bmi-1, and osteogenic progenitor cells (CFU-f) were increased in p27(-/-) Pthrp KI mice compared to Pthrp KI mice.
Conclusions:
- p27 deletion partially rescues skeletal growth retardation and defective osteoblastic bone formation in Pthrp KI mice.
- The rescue effect is mediated by enhanced endochondral bone formation and osteogenesis.
- The p27 pathway likely functions downstream of PTHrP signaling in regulating skeletal growth and development.
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