Endochondral ossification is a fundamental bone forming process involved in normal bone development. It is also recapitulated in pathological conditions such as bone fracture healing and osteophyte formation in osteoarthritis. The precise sources of osteoblasts responsible for trabecular bone formation during endochondral ossification remain not fully defined. Our recent genetic studies provide strong in vivo evidence in support of the hypothesis that a significant fraction of hypertrophic chondrocytes have the ability to become osteoblast lineage cells accountable for trabeculae formation in endochondral bones. Our data further suggest the additional hypothesis that during chondrocytes to osteoblasts transdifferentiation, Col10a1-expressing mature chondrocytes may first dedifferentiate to become mesenchymal progenitor cells in the bone marrow before they redifferentiate into osteoblasts. We propose to perform additional genetic experiments to further substantiate our findings and to provide evidence for the two-step hypothesis underlying the proposed transdifferentiation of mature chondrocytes into osteoblast lineage cells during development and postnatal growth. Other experiments will test the additional hypotheses that hypertrophic chondrocytes are a source of osteoblasts in fracture healing and in osteophyte formation in osteoarthritis. Our proposed experiments should lead to a revision of presently accepted concepts regarding the source of osteoblasts in endochondral bones. Our expected results should have a broad impact on the biology and pathogeny of endochondral bones.

Public Health Relevance

The cells which form bones are called osteoblasts but the exact source of these cells in bone formation is not fully defined. We plan to gain additional evidence for the hypothesis that cartilage-forming cells are a physiological source of bone-forming cells and are also involved in bone fracture repair and in formation of osteophytes in osteoarthritis. Our studies should have a broad impact on our understanding of bone biology and bone diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Chen, Faye H
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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Chen, Qin; Sinha, Krishna; Deng, Jian Min et al. (2015) Mesenchymal Deletion of Histone Demethylase NO66 in Mice Promotes Bone Formation. J Bone Miner Res 30:1608-17
Chen, Qin; Zhang, Liping; de Crombrugghe, Benoit et al. (2015) Mesenchyme-specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation. FASEB J 29:2555-65
Sinha, Krishna M; Yasuda, Hideyo; Zhou, Xin et al. (2014) Osterix and NO66 histone demethylase control the chromatin of Osterix target genes during osteoblast differentiation. J Bone Miner Res 29:855-65
Zhou, Xin; von der Mark, Klaus; Henry, Stephen et al. (2014) Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet 10:e1004820
Coşkun, Süleyman; Chao, Hsu; Vasavada, Hema et al. (2014) Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. Cell Rep 9:581-90
Sinha, Krishna M; Zhou, Xin (2013) Genetic and molecular control of osterix in skeletal formation. J Cell Biochem 114:975-84
Chen, Qin; Liu, Wenbin; Sinha, Krishna M et al. (2013) Identification and characterization of microRNAs controlled by the osteoblast-specific transcription factor Osterix. PLoS One 8:e58104
Baek, Wook-Young; Kim, Young-Ji; de Crombrugghe, Benoit et al. (2013) Osterix is required for cranial neural crest-derived craniofacial bone formation. Biochem Biophys Res Commun 432:188-92
Cao, Zhengguo; Zhang, Hua; Zhou, Xin et al. (2012) Genetic evidence for the vital function of Osterix in cementogenesis. J Bone Miner Res 27:1080-92
Tang, Wanjin; Yang, Fan; Li, Yang et al. (2012) Transcriptional regulation of Vascular Endothelial Growth Factor (VEGF) by osteoblast-specific transcription factor Osterix (Osx) in osteoblasts. J Biol Chem 287:1671-8

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