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.
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.
|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|
|Sinha, Krishna M; Yasuda, Hideyo; Coombes, Madelene M et al. (2010) Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase. EMBO J 29:68-79|
|Zhou, Xin; Zhang, Zhaoping; Feng, Jian Q et al. (2010) Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice. Proc Natl Acad Sci U S A 107:12919-24|
|Zhang, Chi; Cho, Kyucheol; Huang, Yehong et al. (2008) Inhibition of Wnt signaling by the osteoblast-specific transcription factor Osterix. Proc Natl Acad Sci U S A 105:6936-41|
|Akiyama, Haruhiko; Stadler, H Scott; Martin, James F et al. (2007) Misexpression of Sox9 in mouse limb bud mesenchyme induces polydactyly and rescues hypodactyly mice. Matrix Biol 26:224-33|
|Kimura, Hiroaki; Akiyama, Haruhiko; Nakamura, Takashi et al. (2007) Tenascin-W inhibits proliferation and differentiation of preosteoblasts during endochondral bone formation. Biochem Biophys Res Commun 356:935-41|
|Kim, Jung-Eun; Nakashima, Kazuhisa; de Crombrugghe, Benoit (2004) Transgenic mice expressing a ligand-inducible cre recombinase in osteoblasts and odontoblasts: a new tool to examine physiology and disease of postnatal bone and tooth. Am J Pathol 165:1875-82|