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Title: The role of Sox9 in osteogenesis
Author: Zhao, Li
ISNI:       0000 0001 3577 5226
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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Bone fOlmation is an exquisitely coordinated process involving both chondrogenic and osteogenic differentiation. SOX9 is the best-known master regulator for chondrocyte differentiation and cartilage formation. Herein we demonstrate that SOX9 also participates in osteogenic differentiation;bone formation, and the action is interlocked with cAMPIPKA signaling at multilevel. Together with osteogenic markers such as Runx2, ColI a I and osteopontin, SOX9 was up-regulated in the early osteogenic stage of primary MSCs as well as in BMP-2-indued osteoblast differentiation ofC3HlOTl/2 and C2C12 cells. Overexpression of wild-type SOX9 in the progenitor cells efficiently propelled expression of multiple osteogenic marker genes such as ALP activity, type I collagen and osteocalcin expression. The promoter of the type I collagen gene was activated by SOX9. However, pathogenic mutants showed impaired osteogenesis. Furthermore, SOX9 knockdown in the bone progenitor cells inhibited osteogenic differentiation. In vivo, SOX9 overexpression in C3HIOTl12 cells slightly increased bone formation quantity, while SOX9 knockdown significantly blocked development of bone. During signaling investigation, we found the removal of PKA-phosphorylation sites of SOX9 deprived it of stimulatory effect. Chemicals specifically activating or inhibiting PKA signaling and the cognate inhibitor of PKA, PKIy, distinctly affected the SOX9 action. Fmihennore, we provide evidence that through i,ts carboxyl tenninal domain, SOX9 physically and functionally interacts with CREB, the prototypical PKA-downstream transcription factor. Thus, these results suggest that in addition to the predominate role in driving chondrogenesis, SOX9 also plays a novel role by promoting osteogenesis, which is, at both the nuclear and cytoplasmic levels, orchestrated with the PKA pathway during bone formation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available