Postive and Negative Control of Chondrocyte Maturation

软骨细胞成熟的正控制和负控制

• 批准号: 6861059
• 负责人: SHERRILL L. ADAMS
• 金额: $ 31.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-07 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861059
• 关键词: biological signal transduction; bone morphogenetic proteins; cell differentiation; chondrocytes; collagen; genetic transcription; nucleic acid sequence; osteogenesis; parathyroid hormone related protein; retinoate; tissue /cell culture; transcription factor

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.

描述：（由申请人提供）内软骨​​骨形成是一个复杂的 中间细胞分化为软骨细胞的过程；这 软骨细胞发生成熟，变得肥厚并引发 X型胶原蛋白的产生；然后，软骨矩阵然后被钙化并 矿化基质被骨骼代替。软骨细胞的速率 通过这些步骤的进展必须得到准确的监管，因为此过程 确定骨骼的最终大小和形状。信号分子 印度刺猬（IHH）和甲状旁腺相关肽（PTHRP）预防 软骨细胞向肥大态的进展，而视黄酸 （RA），骨形态发生蛋白（BMP）和转录因子CBFAL 加速过渡。关于这些集成知之甚少 信号通路或它们调节的分子机制 软骨细胞的成熟。我们的初步结果表明了一个模型 通过阻断抑制性IHH/PTHRP信号来调节软骨细胞的成熟 途径并激活刺激BMP/CBFAL信号通路。 具体而言，RA可能会抑制IHH的产生，减少PTHRP，从而减少 减轻肥大的抑制，并诱导BMP信号传导和CBFAL， 因此加速成熟。我们将使用转录检验此假设 X型胶原蛋白基因作为控制软骨细胞的范例 成熟。我们建议识别DNA序列和转录因子 RA和BMP刺激X型胶原基因转录所必需的 对于PTHRP的抑制，我们还将检查RA的影响 BMP和PTHRP信号通路的组件，并确定是否 BMP和PTHRP信号传导的抑制剂干扰X型的RA调制 胶原蛋白启动子功能。这些实验对于理解很重要 胚胎发育过程中的软骨内骨形成，也可能提供 深入了解调节断裂修复的机制，这部分发生 通过概括内软骨骨化。另外，这些研究 可能会增加对导致肥厚状态的机制的见解 在骨关节炎中。