Osteogenesis imperfecta (OI) is a family of rare heritable skeletal disorders associated with dominant mutations in the collagen type I encoding genes and recessive defects in proteins involved in collagen type I synthesis and processing and in osteoblast differentiation and activity. Historically, it was believed that the OI bone phenotype was only caused by abnormal collagen type I fibrils in the extracellular matrix, but more recently it became clear that the altered bone cell homeostasis, due to mutant collagen retention, plays a relevant role in modulating disease severity in most of the OI forms and it is correlated to impaired bone cell differentiation. Despite in vitro evidence, in vivo data are missing. To better understand the physiopathology of OI, we used two zebrafish models: Chihuahua (Chi/+), carrying a dominant p.G736D substitution in the α1 chain of collagen type I, and the recessive p3h1^−/−, lacking prolyl 3-hydroxylase (P3h1) enzyme. Both models share the delay of collagen type I folding, resulting in its overmodification and partial intracellular retention. The regeneration of the bony caudal fin of Chi/+ and p3h1^−/− was employed to investigate the impact of abnormal collagen synthesis on bone cell differentiation. Reduced regenerative ability was evident in both models, but it was associated to impaired osteoblast differentiation and osteoblastogenesis/adipogenesis switch only in Chi/+. On the contrary, reduced osteoclast number and activity were found in both models during regeneration. The dominant OI model showed a more detrimental effect in the extracellular matrix organization. Interestingly, the chemical chaperone 4-phenylbutyrate (4-PBA), known to reduce cellular stress and increase collagen secretion, improved bone formation only in p3h1^−/− by favoring caudal fin growth without affecting bone cell markers expression. Taken together, our in vivo data proved the negative impact of structurally abnormal collagen type I on bone formation but revealed a gene mutation-specific effect on bone cell differentiation and matrix organization in OI. These, together with the distinct ability to respond to the chaperone treatment, underline the need for precision medicine approaches to properly treat the disease.

成骨不全症 (OI) 是一类罕见的遗传性骨骼疾病，与 I 型胶原编码基因的显性突变以及参与 I 型胶原合成和加工以及成骨细胞分化和活性的蛋白质的隐性缺陷相关。历史上，人们认为 OI 骨表型仅由细胞外基质中异常的 I 型胶原纤维引起，但最近人们清楚，由于突变胶原蛋白保留而导致的骨细胞稳态改变在调节疾病中发挥着相关作用大多数成骨不全症的严重程度与骨细胞分化受损有关。尽管有体外证据，但在体内数据丢失。为了更好地了解 OI 的生理病理学，我们使用了两种斑马鱼模型：吉娃娃( Chi/+ )，在 I 型胶原蛋白的 α1 链中携带显性 p.G736D 取代，以及隐性p3h1 ^−/−，缺乏脯氨酰 3-羟化酶(P3h1) 酶。两种模型都存在 I 型胶原蛋白折叠延迟的问题，导致其过度修饰和部分细胞内保留。Chi/+和p3h1 ^−/−骨性尾鳍的再生用于研究胶原蛋白合成异常对骨细胞分化的影响。两种模型中再生能力均明显降低，但仅在Chi/+中与成骨细胞分化受损和成骨细胞生成/脂肪生成转换相关。相反，在再生过程中，两种模型中的破骨细胞数量和活性均减少。占主导地位的成骨不全模型对细胞外基质组织表现出更有害的影响。有趣的是，化学伴侣 4-苯基丁酸酯 (4-PBA) 已知可以减少细胞应激并增加胶原蛋白分泌，仅在p3h1 ^−/−中通过促进尾鳍生长而不影响骨细胞标记物表达来改善骨形成。综合起来，我们的体内数据证明了结构异常的 I 型胶原蛋白对骨形成的负面影响，但揭示了基因突变对成骨不全症中骨细胞分化和基质组织的特异性影响。这些，加上对伴侣治疗的独特反应能力，强调需要精准医学方法来正确治疗该疾病。