Effect of rapamycin on bone mass and strength in the α2(I)-G610C mouse model of osteogenesis imperfecta.

John F Bateman,Natalie A Sims,Aaron Schindeler,Shireen R Lamandé,Antonio Maurizi,Tegan L Cheng,Lisa Sampurno,David G Little

doi:10.1111/jcmm.14072

Abstract

Osteogenesis imperfecta (OI) is commonly caused by heterozygous type I collagen structural mutations that disturb triple helix folding and integrity. This mutant‐containing misfolded collagen accumulates in the endoplasmic reticulum (ER) and induces a form of ER stress associated with negative effects on osteoblast differentiation and maturation. Therapeutic induction of autophagy to degrade the mutant collagens could therefore be useful in ameliorating the ER stress and deleterious downstream consequences. To test this, we treated a mouse model of mild to moderate OI (α2(I) G610C) with dietary rapamycin from 3 to 8 weeks of age and effects on bone mass and mechanical properties were determined. OI bone mass and mechanics were, as previously reported, compromised compared to WT. While rapamycin treatment improved the trabecular parameters of WT and OI bones, the biomechanical deficits of OI bones were not rescued. Importantly, we show that rapamycin treatment suppressed the longitudinal and transverse growth of OI, but not WT, long bones. Our work demonstrates that dietary rapamycin offers no clinical benefit in this OI model and furthermore, the impact of rapamycin on OI bone growth could exacerbate the clinical consequences during periods of active bone growth in patients with OI caused by collagen misfolding mutations.

Highlights

Osteogenesis imperfecta (OI) is a serious inherited “brittle bone” disease most commonly resulting from mutations that compromise the function of type I collagen, either by reducing expression of COL1A1 or COL1A2, or causing mutant protein misfolding and degradation.[1]
We treat the α2(I)‐G610C OI mice with rapamycin for 5 weeks from weaning and measure the effect of this treatment on the structure and mechanical properties of the long bones and vertebrae to determine if rapamycin stimulation of autophagy is a viable new clinical approach in the treatment of OI caused by collagen I misfolding/aggregation mutations
While bisphosphonates offer a therapeutic approach, they do not resolve the fundamental issue of reduced bone quality such as that caused by collagen structural mutations

Summary

| INTRODUCTION

Osteogenesis imperfecta (OI) is a serious inherited “brittle bone” disease most commonly resulting from mutations that compromise the function of type I collagen, either by reducing expression of COL1A1 or COL1A2, or causing mutant protein misfolding and degradation.[1]. Recent studies on a mouse model of mild to moderate OI (OI type IV) has yielded important information on disease mechanisms and possible therapeutic approaches.[8] This model features a Col1a2 triple helical codon 610 Gly to Cys substitution (α2(I) G610C), corresponding to a mutation first identified in an Amish family.[9] The α2(I) G610C mutation disturbs the collagen triple helix and results, as expected, in ER accumulation of the mutant‐containing misfolded collagen trimers This results in an unusual form of ER stress which does not involve the canonical unfolded protein response (UPR).[8] This unconventional ER stress response involves modest up‐regulation of CHOP, eIF2α phosphorylation, and chaperones αβ crystalline and HSP47. We treat the α2(I)‐G610C OI mice with rapamycin for 5 weeks from weaning and measure the effect of this treatment on the structure and mechanical properties of the long bones and vertebrae to determine if rapamycin stimulation of autophagy is a viable new clinical approach in the treatment of OI caused by collagen I misfolding/aggregation mutations

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION