DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide
| Autor: | Zhen Gu, David Goltzman, Haijian Sun, Ying Zhang, Guangpei Chen, Dengshun Miao, Andrew C. Karaplis |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Osteoclasts Apoptosis medicine.disease_cause Applied Microbiology and Biotechnology skeletal growth Antioxidants Histones Mice Osteogenesis Gene expression Cellular Senescence Chemistry Osteoblast Cell biology medicine.anatomical_structure Female osteoblastic bone formation Type I collagen hormones hormone substitutes and hormone antagonists Research Paper Signal Transduction Senescence musculoskeletal diseases DNA damage PTHrP Chk2 Mice Transgenic 03 medical and health sciences Protein Domains medicine Animals Bone Resorption Molecular Biology Ecology Evolution Behavior and Systematics Cell Proliferation Bone Development Osteoblasts Gene Expression Profiling Parathyroid Hormone-Related Protein Cell Biology Cell Cycle Checkpoints G2-M DNA damage checkpoint Mice Inbred C57BL Checkpoint Kinase 2 Oxidative Stress 030104 developmental biology Tumor Suppressor Protein p53 Reactive Oxygen Species Oxidative stress Nuclear localization sequence Gene Deletion Developmental Biology DNA Damage |
| Zdroj: | International Journal of Biological Sciences |
| ISSN: | 1449-2288 |
| Popis: | We previously demonstrated that parathyroid hormone-related peptide (PTHrP) 1-84 knockin (Pthrp KI) mice, which lacked a PTHrP nuclear localization sequence (NLS) and C-terminus, displayed early senescence, defective osteoblastic bone formation, and skeletal growth retardation. However, the mechanism of action of the PTHrP NLS and C-terminus in regulating development of skeleton is still unclear. In this study, we examined alterations of oxidative stress and DNA damage response-related molecules in Pthrp KI skeletal tissue. We found that ROS levels, protein expression levels of γ-H2AX, a DNA damage marker, and the DNA damage response markers p-Chk2 and p53 were up-regulated, whereas gene expression levels of anti-oxidative enzymes were down-regulated significantly. We therefore further disrupted the DNA damage response pathway by deleting the Chk2 in Pthrp KI (Chk2-/-KI) mice and did comparison with WT, Chk2-/- and Pthrp KI littermates. The Pthrp KI mice with Chk2 deletion exhibited a longer lifespan, improvement in osteoblastic bone formation and skeletal growth including width of growth plates and length of long bones, trabecular and epiphyseal bone volume, BMD, osteoblast numbers, type I collagen and ALP positive bone areas, the numbers of total colony-forming unit fibroblasts (CFU-f), ALP+ CFU-f and the expression levels of osteogenic genes. In addition, the genes associated with anti-oxidative enzymes were up-regulated significantly, whereas the tumor suppressor genes related to senescence were down-regulated in Chk2-/- KI mice compared to Pthrp KI mice. Our results suggest that Chk2 deletion in Pthrp KI mice can somewhat rescue defects in osteoblastic bone formation and skeletal growth by enhancing endochondral bone formation and osteogenesis. These studies therefore indicate that the DNA damage checkpoint pathway may be a target for the nuclear action of PTHrP to regulate skeletal development and growth. |
| Databáze: | OpenAIRE |
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