Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility and skeletal deformity. To maintain skeletal strength and integrity, bone undergoes constant remodeling of its extracellular matrix (ECM) tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. There are at least 20 recognized OI-forms caused by mutations in the two collagen type I-encoding genes or genes implicated in collagen folding, posttranslational modifications or secretion of collagen, osteoblast differentiation and function, or bone mineralization. The underlying disease mechanisms of non-classical forms of OI that are not caused by collagen type I mutations are not yet completely understood, but an altered ECM structure as well as disturbed intracellular homeostasis seem to be the main defects. The ECM orchestrates local cell behavior in part by regulating bioavailability of signaling molecules through sequestration, release and activation during the constant bone remodeling process.

Here, we provide an overview of signaling pathways that are associated with known OI-causing genes and discuss the impact of these genes on signal transduction. These pathways include WNT-, RANK/RANKL-, TGFβ-, MAPK- and integrin-mediated signaling as well as the unfolded protein response.

成骨不全症 (OI) 是一种临床和遗传异质性结缔组织疾病，其特征是骨脆性和骨骼畸形。为了保持骨骼强度和完整性，骨骼会不断重塑其细胞外基质 (ECM)，这受到破骨细胞介导的骨吸收和成骨细胞介导的骨形成的严格控制。至少有 20 种公认的 OI 形式是由两种 I 型胶原蛋白编码基因或与胶原蛋白折叠、翻译后修饰或胶原蛋白分泌、成骨细胞分化和功能或骨矿化有关的基因突变引起的。并非由 I 型胶原蛋白突变引起的非经典形式的 OI 的潜在疾病机制尚未完全了解，但改变的 ECM 结构以及扰乱的细胞内稳态似乎是主要缺陷。ECM 部分地通过在持续的骨重塑过程中通过隔离、释放和激活来调节信号分子的生物利用度来协调局部细胞行为。

在这里，我们概述了与已知的 OI 致病基因相关的信号通路，并讨论了这些基因对信号转导的影响。这些通路包括 WNT-、RANK/RANKL-、TGFβ-、MAPK-和整合素介导的信号传导以及未折叠蛋白反应。