Genetic Control of Osteoblast Differentiation

描述（由申请人提供）：软骨内成骨是正常骨发育的基本骨形成过程。它也被概括在病理条件下，如骨折愈合和骨关节炎的骨赘形成。软骨内成骨过程中负责骨小梁形成的成骨细胞的确切来源尚未完全确定。我们最近的遗传学研究提供了强有力的体内证据，支持了一种假设，即很大一部分肥大软骨细胞具有成为成骨细胞谱系的能力，负责软骨内骨小梁的形成。我们的数据进一步提出了另一种假设，即在软骨细胞向成骨细胞转分化过程中，表达col10a1的成熟软骨细胞可能首先去分化为骨髓中的间充质祖细胞，然后再分化为成骨细胞。我们建议进行额外的基因实验来进一步证实我们的发现，并为成熟软骨细胞在发育和出生后生长过程中向成骨细胞谱系细胞转分化的两步假说提供证据。其他的实验将验证增生性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这一附加假设。我们提出的实验应该导致对目前公认的关于软骨内骨成骨细胞来源的概念的修订。我们预期的结果将对软骨内骨的生物学和发病机制产生广泛的影响。

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.