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Human macrophage metalloelastase (MMP-12) expression is induced in chondrocytes during fetal development and
E Kerkelä1, T Böhling, R Herva
1Department of Dermatology Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Abstract:
Fetal development and tumor progression both require a complex system of extracellular matrix (ECM) synthesis and breakdown, which is mediated by, for instance, the matrix metalloproteinases (MMPs). Human metalloelastase (MMP-12) is an MMP, the expression of which has so far been documented in macrophages associated with atherosclerosis, wound repair, and certain cancers. In this study we first examined the expression of MMP-12 during human fetal development. By in situ hybridization MMP-12 transcripts were detected in chondrocytes of hypertrophic cartilage in vertebrae of the spinal column, in ribs, and in extremities undergoing ossification, beginning at the gestational age of 8 weeks. Also, periosteal cells expressed MMP-12 at 11 weeks. No expression of MMP-12 mRNA could be noted in other fetal tissues, including the skin, lungs, intestine, kidney, and liver. Expression of MMP-12 mRNA could not be detected in adult normal cartilage or osteosarcomas, but in chondrosarcomas both macrophages (8 of 19 samples) (identified by CD68 immunostaining) and chondrosarcoma cells (8 of 19) were positive. MMP-12 was also demonstrated in the tumors by western blotting and it was expressed in the same regions as MMP-13 mRNA. By immunostaining, MMP-12 mRNA colocalized with the protein in both fetal and chondrosarcoma specimens. Unlike basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) induced MMP-12 mRNA production in chondrosarcoma-derived HTB-94 cells. Our results suggest that MMP-12 plays an important role in ECM remodeling during fetal bone development and is induced when chondrocytes undergo malignant transformation.
Insights
Matrix metalloproteinase-12 (MMP-12) is crucial for fetal bone development and is induced in chondrosarcomas, suggesting a role in both normal development and cancer progression.
Area of Science:
- Biochemistry
- Developmental Biology
- Oncology
Background:
- Extracellular matrix (ECM) remodeling is vital for fetal development and tumor growth.
- Matrix metalloproteinases (MMPs) mediate ECM synthesis and breakdown.
- Human metalloelastase (MMP-12) expression is known in macrophages involved in atherosclerosis, wound repair, and some cancers.
Purpose of the Study:
- To investigate the expression of MMP-12 during human fetal development.
- To examine MMP-12 expression in chondrosarcomas and its regulation.
Main Methods:
- In situ hybridization to detect MMP-12 mRNA in fetal tissues.
- Immunohistochemistry and Western blotting to analyze MMP-12 protein in chondrosarcomas.
- Cell culture experiments with chondrosarcoma cells to study MMP-12 induction.
Main Results:
- MMP-12 mRNA was detected in chondrocytes of developing vertebrae, ribs, and extremities from 8 weeks of gestation.
- Periosteal cells expressed MMP-12 at 11 weeks of gestation.
- MMP-12 was found in macrophages and chondrosarcoma cells in human chondrosarcomas, but not in normal adult cartilage or osteosarcomas.
- Tumor necrosis factor-alpha (TNF-alpha) induced MMP-12 mRNA production in chondrosarcoma cells.
Conclusions:
- MMP-12 plays a significant role in extracellular matrix remodeling during fetal bone development.
- MMP-12 is induced in chondrocytes during malignant transformation, indicating its involvement in chondrosarcoma development.