| First Author | Boraschi-Diaz I | Year | 2021 |
| Journal | Bone | Volume | 145 |
| Pages | 115867 | PubMed ID | 33524637 |
| Mgi Jnum | J:305162 | Mgi Id | MGI:6514946 |
| Doi | 10.1016/j.bone.2021.115867 | Citation | Boraschi-Diaz I, et al. (2021) Effects of treatment with a bone-targeted prostaglandin E2 receptor 4 agonist C3 (Mes-1007) in a mouse model of severe osteogenesis imperfecta. Bone 145:115867 |
| abstractText | OBJECTIVE: Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I synthesis in osteoblasts. Bisphosphonates are widely used to decrease fracture rate but are only partially effective. Bone anabolic compounds, such as prostaglandin E2 receptor 4 (EP4) agonists may be an alternative treatment approach. Here we assessed the effect of Mes-1007, a novel bone-targeted EP4 agonist in Jrt mice, a model of severe OI. STUDY DESIGN: Experimental study. RESULTS: Male 8-week old wild type (WT) and OI mice were randomly assigned to 4 weeks of three intraperitoneal injections per week with Mes-1007 (25 mg per kg body mass), phosphate-buffered saline, zoledronate (5 mug per kg), or a combination treatment of zoledronate and Mes-1007. Treatment with Mes-1007 alone did not lead to higher trabecular bone volume per tissue volume (BV/TV) in the distal femur or lumbar vertebra 4 in either WT or OI mice. Treatment with zoledronate alone was associated with a significant increase in distal femur and vertebra BV/TV in both genotypes. In zoledronate-treated WT and OI mice, Mes-1007 increased bone formation rate in vertebral trabecular bone and had an additive effect on BV/TV. Vertebral BV/TV in OI mice that received zoledronate or Mes-1007/zoledronate combination treatment was similar to untreated WT mice (p = 0.25). At the femoral midshaft, Mes-1007/zoledronate combination treatment increased cortical thickness in both genotypes and led to higher periosteal diameter in OI mice. Three-point bending tests of femurs showed that Mes-1007/zoledronate combination treatment increased the stiffness, load at yield and maximal load in WT but not in OI mice. CONCLUSION: Dosing Mes-1007 in combination with zoledronate improved the bone properties in a manner that is consistent with a mechanism of action of EP4 agonists on bone and additive to effects of anti-resorptives typified by zoledronate. |
