Genetic Control of Osteoblast Differentiation

描述(申请人提供)：软骨内骨化是一个基本的骨形成过程，涉及正常的骨发育。它也在骨关节炎的骨折愈合和骨赘形成等病理条件下得到重现。在软骨内骨化过程中，负责骨小梁形成的成骨细胞的确切来源仍未完全确定。我们最近的遗传学研究提供了强有力的体内证据，支持这样的假设，即相当一部分肥大的软骨细胞有能力成为成骨细胞系细胞，负责软骨内骨中小梁的形成。我们的数据进一步表明，在软骨细胞向成骨细胞转分化的过程中，表达COL10a1的成熟软骨细胞可能首先去分化，成为骨髓中的间充质前体细胞，然后再分化为成骨细胞。我们建议进行更多的遗传学实验，以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转分化为成骨细胞系细胞的两步假说提供证据。其他实验将检验额外的假设，即肥大的软骨细胞是骨折愈合和骨关节炎骨赘形成过程中成骨细胞的来源。我们提议的实验应该导致对目前被接受的关于软骨内骨中成骨细胞来源的概念的修订。我们的预期结果应该会对软骨内骨的生物学和病因学产生广泛的影响。

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.