Genetic Control of Osteoblast Differentiation

描述（由申请方提供）：软骨内骨化是正常骨发育中涉及的基本骨形成过程。它也在病理条件下，如骨折愈合和骨关节炎中的骨赘形成中重演。在软骨内骨化过程中负责小梁骨形成的成骨细胞的确切来源仍然没有完全确定。我们最近的遗传学研究提供了强有力的体内证据，支持这一假设，即一个显着的比例肥大的软骨细胞有能力成为成骨细胞谱系细胞负责骨小梁形成内软骨骨。我们的数据进一步表明，在软骨细胞成骨细胞转分化，Col10a1表达的成熟软骨细胞可能首先去分化成为骨髓间充质祖细胞，然后再分化成成骨细胞的额外的假设。我们建议进行额外的遗传实验，以进一步证实我们的研究结果，并提供证据的两步假说的基础上提出的转分化成熟软骨细胞成骨细胞谱系细胞在发展和出生后的增长。其他实验将测试额外的假设，即肥大软骨细胞是骨折愈合和骨关节炎骨赘形成中成骨细胞的来源。我们提出的实验应导致目前公认的概念，在软骨内骨成骨细胞的来源进行修订。我们的预期结果应该有广泛的影响，生物学和病因的软骨内骨。

DESCRIPTION (provided by applicant): 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.