Postive and Negative Control of Chondrocyte Maturation

描述：(申请人提供)软骨内骨形成是一种复合体 间充质细胞分化为软骨细胞的过程； 软骨细胞经历成熟、肥大和启动 产生X型胶原；然后软骨基质变得钙化， 矿化的基质被骨取代。软骨细胞的速率 必须对通过这些步骤取得的进展进行精确管理，因为这一过程 确定骨骼的最终大小和形状。信号分子 印度刺猬(IHH)和甲状旁腺素相关肽(PTHrP)预防 软骨细胞向高营养状态的进展，而维甲酸 (RA)、骨形成蛋白(BMPs)和转录因子Cbfal 加快转型。人们对它们的整合知之甚少 信号通路或其调节的分子机制 软骨细胞成熟。我们的初步结果表明，RA的模型 通过阻断抑制的IHH/PTHrP信号调节软骨细胞成熟 激活刺激性BMP/Cbfal信号通路。 具体地说，RA可以抑制IHH的产生，减少PTHrP，从而 减轻肥厚抑制，诱导BMP信号转导和Cbfal， 从而加速成熟。我们将使用转录来检验这一假设 X型胶原基因作为控制软骨细胞的范例 成熟。我们建议鉴定DNA序列和转录因子 RA和BMPs刺激X型胶原基因转录所需 对于PTHrP的抑制，我们还将研究RA对 BMP和PTHrP信号通路的组成并确定 BMP和PTHrP信号的抑制剂干扰X型RA的调节 胶原蛋白的促进剂作用。这些实验对于理解 胚胎发育过程中软骨内骨的形成，也可能提供 洞察调控骨折修复的机制，这在一定程度上发生在 通过对软骨内骨化的重述。此外，这些研究 可能增加对导致肥厚样状态的机制的洞察力 骨性关节炎。

DESCRIPTION: (provided by applicant) Endochondral bone formation is a complex process in which mesenchyrnal cells differentiate into chondrocytes; the chondrocytes undergo maturation, becoming hypertrophic and initiating production of type X collagen; the cartilage matrix then becomes calcified and the mineralized matrix is replaced by bone. The rate at which chondrocytes progress through these steps must be precisely regulated, since this process determines the ultimate size and shape of the bone. The signaling molecules Indian hedgehog (Ihh) and parathyroid hormone related peptide (PTHrP) prevent progression of chondrocytes to the hypertropbic state, while retinoic acid (RA), bone morphogenetic proteins (BMPs) and the transcription factor Cbfal accelerate the transition. Little is known about the integration of these signaling pathways or the molecular mechanisms by which they regulate chondrocyte maturation. Our preliminary results suggest a model in which RA regulates chondrocyte maturation by blocking the inhibitory Ihh/PTHrP signaling pathway and activating the stimulatory BMP/Cbfal signaling pathway. Specifically, RA may inhibit production of Ihh, reducing PTHrP and thus relieving the repression of hypertrophy, and induce BMP signaling and Cbfal, thus accelerating maturation. We will test this hypothesis using transcription of the type X collagen gene as a paradigm for control of chondrocyte maturation. We propose to identify the DNA sequences and transcription factors required for stimulation of type X collagen gene transcription by RA and BMPs and for repression by PTHrP We will also examine the effects of RA on components of the BMP and PTHrP signaling pathways and determine whether inhibitors of BMP and PTHrP signaling interfere with RA modulation of type X collagen promoter function. These experiments are important for understanding endochondral bone formation during embryonic development, and may also provide insight into the mechanisms that regulate fracture repair, which occurs in part by a recapitulation of endochondral ossification. In addition, these studies may increase insight into the mechanisms that lead to a hypertrophic-like state in osteoarthritis.