Project Summary
There is no cure for osteogenesis imperfecta (OI or brittle bone disease), the most common of the heritable
disorders of bone affecting 1:15,000 births. The most evident clinical hallmarks of OI is bone fragility and skeletal
deformities. OI is caused primarily by defects in collagen type I, leading to collagen molecules folding improperly,
disrupting fibril alignment and structure, and providing an abnormal template for mineralization in bone. For this
reason, OI has been traditionally considered a bone extracellular matrix disorder, and current treatments for OI
rely on the use of pharmacological drugs, mainly bisphosphonates, a class of drugs that inhibit bone resorption
and is used in the management of osteoporosis. Despite the initial success, the actual efficacy of these
treatments to reduce the fracture risk are controversial and additional risks may arise from the long-term use of
this drug in developing bones of children with OI. Recent research has demonstrated a cellular component to
the OI disease: the endoplasmic reticulum (ER) stress in the osteoblasts of OI bone. We also recently found that
pharmacological action toward ER stress using the 4-phenyl butyrate (4PBA) is able to reduce the OI phenotype
severity, increasing bone formation and reducing skeletal deformities. This drug treatment needs two
improvements: 1) increase its stability and 2) make it able to effectively reach the bone. Furthermore, unknown
is the effect of the treatment on bone quality and mechanics.
The rationale of the proposed experiments is to synthesize a 4PBA derivative, the N-benzyl glycine (N-BG), that
is more stable and to determine its effect on OI ER cells stress and on OI bone material properties. In a second
experiment, we will test the efficacy of a carrier ((GfO)8) to deliver N-BG to bone cells and the effect on OI bone
quality. We will use primary isolated osteoblasts from Brtl mouse model of OI for the in vitro testing of ER and
apoptotic stress with N-BG. Zebrafish models of recessive (p3h1-/-) and dominant (Chihuahua) type of OI, and
healthy zebrafishes will be injected with either placebo or N-BG drug or (GfO)8-N-BG drug+carrier. Morphology
and tissue porosity of precaudal vertebrae will be analyzed in the treated zebrafishes and the c
hanges with drug
therapy to the collagen fiber organization, bone tissue composition and mechanical properties will be examined
using an array of high resolution experiments.
The knowledge gained from this study will inform on the efficacy
of new 4PBA derivatives therapies and on the use of carriers to treat bone fragility in OI. This work will also
provide the first and standardized pipeline to evaluate drug effect on Zebrafish skeletal disease models.