TGF-β signaling inhibits osteoanabolic response to PTH in Osteogenesis Imperfecta

成骨不全(OI)是一种以骨量减少、骨机械强度受损和骨折为特征的遗传性疾病。此外，OI骨显示骨细胞密度增加，骨细胞驻留在矿化骨基质内的陷窝中，并控制骨重建。有趣的是，OI骨中的陷窝形态也发生了变化，提示骨细胞功能异常。大多数OI病例是由I型胶原编码基因的常染色体显性突变引起的。隐性OI可由涉及翻译后胶原蛋白修饰的基因突变引起。此前，我们发现转化生长因子-β信号的增加是导致显性和隐性中/重度OI小鼠OI表型的重要因素，抑制转化生长因子-β可以改善骨量和强度，并使骨细胞密度正常化。间歇性甲状旁腺激素可增加骨质疏松和轻度OI患者的骨密度，但对较严重的OI患者无效。中/重度OI患者对甲状旁腺素治疗产生这种抵抗的原因尚不清楚。有趣的是，转化生长因子-β和甲状旁腺素信号通路相互作用来调节骨重建，这两个通路都参与了骨细胞的功能。我们假设：(I)OI中转化生长因子-β信号的增加是降低甲状旁腺素治疗反应的机制，(Ii)抑制转化生长因子-β可恢复对甲状旁腺素的骨合成代谢效应的反应性，以及(Iii)联合抗转化生长因子-β/甲状旁腺素治疗可改善OI的骨量和强度以及骨细胞表型。为了验证这些假设，我们将(I)确定抑制转化生长因子-β在多大程度上恢复甲状旁腺素治疗对显性和隐性OI小鼠骨数量和质量的反应，(Ii)表征甲状旁腺素信号通路的分子变化以及与转化生长因子-β信号通路的体外和体外相互作用，(Iii)确定抗转化生长因子-β/甲状旁腺素治疗对骨细胞形态和分子表型的影响。该项目将为失控的转化生长因子-β和甲状旁腺素信号之间的相互作用提供新的见解，作为OI的一个机制，并有可能为OI患者提供更好的治疗选择。

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by low bone mass, impaired mechanical bone strength and fractures. Additionally, OI bone exhibits an increased density of osteocytes, cells that reside within lacunae within the mineralized bone matrix and control bone remodeling. Interestingly, also the lacuna morphology is altered in OI bone, suggesting abnormal osteocyte function. Most OI cases are caused by autosomal dominant mutations in the genes encoding type I collagen. Recessive OI can be caused by mutations in genes that are involved in post-translational collagen modifications. Previously, we found that increased TGF-β signaling is an important contributor to the OI phenotype in mouse models of both dominant and recessive moderate/severe OI, and TGF-β inhibition improved bone mass and strength, and normalized osteocyte density. Intermittent PTH increases bone mineral density in patients with osteoporosis and mild OI, but is not effective in patients with more severe forms of OI. The reasons for this resistance to PTH treatment in moderate/severe OI are not known. Interestingly, the TGF-β and PTH signaling pathways interact to modulate bone remodeling and both pathways are involved in osteocyte function. We hypothesize that (I) increased TGF-β signaling in OI is a mechanisms that impairs the response to PTH treatment, (II) that TGF-β inhibition restores responsiveness to the osteoanabolic effects of PTH, and (III) that combined anti-TGF-β/PTH treatment improves bone mass and strength as well as the osteocyte phenotype in OI. To test these hypotheses, we will (i) determine to what extent TGF-β-inhibition restores the response to PTH treatment on bone quantity and quality in mouse models of dominant and recessive OI, (ii) characterize the molecular changes in the PTH signaling pathway and the interactions with TGF-β signaling ex vivo and in vitro, and (iii) determine the effects of anti-TGF-β/PTH treatment on the morphological and molecular osteocyte phenotype. This project will provide novel insights into the interactions between dysregulated TGF-β and PTH signaling as a mechanism of OI, and potentially lead to better treatment options for OI patients.