Combined antiresorptive and new anabolic drug approach in osteogenesis imperfecta zebrafish models.

Osteogenesis imperfecta (OI) is a family of heritable collagen I-related skeletal disorders for which, to date, no definitive cure is available. Individuals with OI are mainly treated with bisphosphonates that enhance bone mass by inhibiting bone resorption. However, new strategies combining antiresorptive molecules with bone anabolic drugs are likely to provide valid alternatives for skeletal health, protecting physiological bone turnover. Recently, cellular stress has been identified as a therapeutic target in both dominant and recessive forms of OI characterized by overmodified collagen I. The chemical chaperone 4-phenylbutyrate (4PBA) successfully ameliorated cell homeostasis in both in vitro and in vivo OI models. In this study, dominant Chihuahua (Chi/+) and recessive p3h1^-/- zebrafish OI models were treated for 2 mo either with the bisphosphonate alendronate (ALN) or with 4PBA or with a combination of the two. The treatment effect at the tissue level was evaluated by microCT analysis of the vertebral body, while histology and gene expression analyses allowed to dissect the consequences at a cellular level. Only ALN administration improved the vertebral thickness in the dominant Chi/+ model. The combined therapy synergistically improved osteoblast homeostasis and promoted the formation of mature extracellular collagen fibers in both models. All treatment conditions reduced osteoclast TRAP activity in Chi/+, whereas 4PBA and 4PBA + ALN had the opposite effect on p3h1^-/- . Finally, 4PBA and the combination of ALN and 4PBA reduced osteocyte apoptosis only in p3h1^-/- . Our data demonstrated for the first time in vivo a differential effect of the combination of an antiresorptive and a new anabolic compound in dominant and recessive OI zebrafish models, stressing the importance of identifying the specific causative molecular defect to define the best treatment option.