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Isolation of Mesenchymal Stem Cells from Human Alveolar Periosteum and Effects of Vitamin D on Osteogenic Activity of Periosteum-derived Cells
Published on: May 4, 2018
Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in
Xinping Zhang1, Edward M Schwarz, Donald A Young
1The Center for Musculoskeletal Research, University of Rochester Medical Center, New York 14642, USA.
Abstract:
Preclinical and clinical studies suggest a possible role for cyclooxygenases in bone repair and create concerns about the use of nonsteroidal antiinflammatory drugs in patients with skeletal injury. We utilized wild-type, COX-1(-/-), and COX-2(-/-) mice to demonstrate that COX-2 plays an essential role in both endochondral and intramembranous bone formation during skeletal repair. The healing of stabilized tibia fractures was significantly delayed in COX-2(-/-) mice compared with COX-1(-/-) and wild-type controls. The histology was characterized by a persistence of undifferentiated mesenchyme and a marked reduction in osteoblastogenesis that resulted in a high incidence of fibrous nonunion in the COX-2(-/-) mice. Similarly, intramembranous bone formation on the calvaria was reduced 60% in COX-2(-/-) mice following in vivo injection of FGF-1 compared with either COX-1(-/-) or wild-type mice. To elucidate the mechanism involved in reduced bone formation, osteoblastogenesis was studied in bone marrow stromal cell cultures obtained from COX-2(-/-) and wild-type mice. Bone nodule formation was reduced 50% in COX-2(-/-) mice. The defect in osteogenesis was completely rescued by addition of prostaglandin E2 (PGE(2)) to the cultures. In the presence of bone morphogenetic protein (BMP-2), bone nodule formation was enhanced to a similar level above that observed with PGE(2) alone in both control and COX-2(-/-) cultures, indicating that BMPs complement COX-2 deficiency and are downstream of prostaglandins. Furthermore, we found that the defect in COX-2(-/-) cultures correlated with significantly reduced levels of cbfa1 and osterix, two genes necessary for bone formation. Addition of PGE(2) rescued this defect, while BMP-2 enhanced cbfa1 and osterix in both COX-2(-/-) and wild-type cultures. Finally, the effects of these agents were additive, indicating that COX-2 is involved in maximal induction of osteogenesis. These results provide a model whereby COX-2 regulates the induction of cbfa1 and osterix to mediate normal skeletal repair.
Insights
Cyclooxygenase-2 (COX-2) is essential for skeletal repair, as COX-2 deficient mice show delayed bone healing and reduced osteoblastogenesis. Prostaglandin E2 (PGE2) rescues these defects, highlighting COX-2
Area of Science:
- Biochemistry
- Orthopedics
- Molecular Biology
Background:
- Cyclooxygenases (COX) are implicated in bone repair.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) raise concerns for patients with skeletal injuries.
- COX-2's specific role in bone healing requires elucidation.
Purpose of the Study:
- To investigate the role of cyclooxygenase-2 (COX-2) in skeletal repair.
- To determine the impact of COX-2 deficiency on bone formation processes.
- To elucidate the molecular mechanisms underlying COX-2's function in osteogenesis.
Main Methods:
- Utilized wild-type, COX-1 knockout (KO), and COX-2 KO mice.
- Analyzed stabilized tibia fracture healing and calvarial bone formation.
- Examined osteoblastogenesis in bone marrow stromal cell cultures.
- Assessed gene expression of cbfa1 and osterix.
Main Results:
- COX-2 deficient mice exhibited significantly delayed fracture healing and reduced osteoblastogenesis.
- Intramembranous bone formation was reduced by 60% in COX-2 KO mice.
- Defects in osteogenesis and gene expression (cbfa1, osterix) were rescued by prostaglandin E2 (PGE2).
- Bone morphogenetic proteins (BMPs) complemented COX-2 deficiency.
Conclusions:
- COX-2 plays a critical role in both endochondral and intramembranous bone formation during skeletal repair.
- COX-2 regulates osteoblast differentiation and bone healing, partly through PGE2 production.
- Targeting COX-2 may offer therapeutic strategies for enhancing bone repair.
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