Effects of treatment with a bone-targeted prostaglandin E2 receptor 4 agonist C3 (Mes-1007) in a mouse model of severe osteogenesis imperfecta

Iris Boraschi-Diaz; Gang Chen; Jonathan Polak-Nachumow; Robert N Young; Frank Rauch

doi:10.1016/j.bone.2021.115867

Effects of treatment with a bone-targeted prostaglandin E2 receptor 4 agonist C3 (Mes-1007) in a mouse model of severe osteogenesis imperfecta

Bone. 2021 Apr:145:115867. doi: 10.1016/j.bone.2021.115867. Epub 2021 Jan 29.

Authors

Iris Boraschi-Diaz¹, Gang Chen², Jonathan Polak-Nachumow³, Robert N Young², Frank Rauch⁴

Affiliations

¹ Shriners Hospital for Children-Canada, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
² Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada; Mesentech Inc., Vancouver, British Columbia, Canada.
³ Mesentech Inc., Vancouver, British Columbia, Canada.
⁴ Shriners Hospital for Children-Canada, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada. Electronic address: frauch@shriners.mcgill.ca.

PMID: 33524637
DOI: 10.1016/j.bone.2021.115867

Abstract

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 μg 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.

Keywords: Bone remodeling; Fractures; Osteogenesis imperfecta; Prostaglandin E(2).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Density
Bone and Bones
Dinoprostone
Disease Models, Animal
Femur
Male
Mice
Osteogenesis
Osteogenesis Imperfecta* / drug therapy

Substances

Dinoprostone