Prolyl Hydroxylase Domain-Containing Protein 2 (Phd2) Regulates Chondrocyte Differentiation and Secondary Ossification in Mice

• Published in: Scientific reports 2016-10, Vol.6 (1), p.35748-35748, Article 35748
• Main Authors: Cheng, Shaohong, Aghajanian, Patrick, Pourteymoor, Sheila, Alarcon, Catrina, Mohan, Subburaman
• Format: Article
• Language: English
• Subjects: 13; 38; 631/136/142; 631/136/818; 631/443/63; Alkaline phosphatase; Animals; Ascorbic acid; Biomarkers - metabolism; Bone growth; Bone mass; Bone sialoprotein; Cell Differentiation - physiology; Chondrocytes; Chondrocytes - metabolism; Chondrocytes - physiology; Chondrogenesis; Chondrogenesis - physiology; Endochondral bone; Epiphysis; Erythropoietin - metabolism; Gene deletion; Gene expression; Growth Plate - metabolism; Growth Plate - physiology; Humanities and Social Sciences; Hypertrophy; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Hypoxia-inducible factors; Long bone; Mice; Mineralization; Molecular modelling; multidisciplinary; Ossification; Osteoblasts; Osteoblasts - metabolism; Osteoblasts - physiology; Osteogenesis; Osteogenesis - physiology; Prolyl hydroxylase; RNA, Messenger - metabolism; Rodents; Science; Signal Transduction; Tibia - metabolism; Tibia - physiology; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor B - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep35748

Endochondral ossification plays an important role in the formation of the primary ossification centers (POCs) and secondary ossification centers (SOCs) of mammalian long bones. However, the molecular mechanisms that regulate POC and SOC formation are different. We recently demonstrated that Prolyl Hydroxylase Domain-containing Protein 2 ( Phd2 ) is a key mediator of vitamin C effects on bone. We investigated the role of Phd2 on endochondral ossification of the epiphyses by conditionally deleting the Phd2 gene in osteoblasts and chondrocytes. We found that the deletion of Phd2 in osteoblasts did not cause changes in bone parameters in the proximal tibial epiphyses in 5 week old mice. In contrast, deletion of Phd2 in chondrocytes resulted in increased bone mass and bone formation rate (normalized to tissue volume) in long bone epiphyses, indicating that Phd2 expressed in chondrocytes, but not osteoblasts, negatively regulates secondary ossification of epiphyses. Phd2 deletion in chondrocytes elevated mRNA expression of hypoxia-inducible factor (HIF) signaling molecules including Hif-1α , Hif-2α , Vegfa , Vegfb , and Epo , as well as markers for chondrocyte hypertrophy and mineralization such as Col10 , osterix , alkaline phosphatase, and bone sialoprotein. These data suggest that Phd2 expressed in chondrocytes inhibits endochondral ossification at the epiphysis by suppressing HIF signaling pathways.