Increased susceptibility to microdamage in Brtl/+ mouse model for osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a genetic disease of collagen or collagen-related proteins that adversely impacts bone mass and fracture resistance. Little is known regarding the role that microdamage plays in OI and whether or not OI bone is more prone to damage accumulation than bone with unaffected collagen. The Brtl/+ mouse is a heterozygous model for OI which contains a Gly349Cys substitution in one COL1A1 allele, and demonstrates a low ductility phenotype. At 8 weeks of age, Brtl/+ demonstrates an increase in osteoclast number, which mimics the upregulated bone turnover often found in OI patients. We hypothesize that upregulated osteoclast activity in Brtl/+ is due, in part, to increased remodeling associated with microdamage repair. In the present study, we used Brtl/+ to investigate the susceptibility of OI bone to microdamage. The mouse ulnar loading model was used to induce microdamage and to test the hypothesis that Brtl/+ is more susceptible to damage accumulation than age-matched wild type (WT) counterparts. Linear elastic fracture mechanics (LEFM) was used to investigate the fracture toughness properties of both Brtl/+ and WT bones to determine if there is any correlation with toughness and the degree of microdamage. Results show that Brtl/+ ulnae subject to normal cage activity demonstrate an inherently larger amount of microdamage than WT controls. Following axial compressive loading, Brtl/+ ulnae are more prone to damage than WT counterparts despite demonstrating a greater resistance to whole-bone deformation. Fracture toughness results demonstrate that Brtl/+ specimens, despite not exhibiting a significant difference, display a trend toward lower fracture toughness values than their WT counterparts. Correlations show that microdamage levels tend to increase as fracture toughness decreases. Together, these findings may have strong clinical implications for explaining increased fragility and remodeling activity in OI patients.

Mineral and Matrix Changes in Brtl/+Teeth Provide Insights into Mineralization Mechanisms

“…Their bones also sustain more microdamage than the WT [32]. The respective failure of the odontoblasts to make the physiologic type I collagen trimer results in dental abnormalities and tooth discolorations in patients with all types of the classic OI types [33].…”

Extracellular matrix networks in bone remodeling

“…Clinically, OI patients can encounter numerous fractures through life (Rauch and Glorieux, 2004). Structural deficiencies such as thinner bone cortices and osteoporotic-like trabecular bone mass have been described in OI, but microcracking of the bone itself has been observed in animal models of the disease (Davis et al, 2012;Dong et al, 2010). Elevated levels of microcracks within OI bone have been postulated as a mechanism responsible for the observations of elevated bone turnover, perhaps due to attempts to target these sites for repair (Rauch and Glorieux, 2004).…”

Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment

“…Brtl/+ recapitulates many of the phenotypic features of pediatric OI including small size, impaired remodeling, reduced trabecular and cortical bone mass, altered bone matrix structure, and impaired fracture mechanics (20–23). As such, Brtl/+ has been used to explore multiple clinically relevant questions including fracture repair (24), bisphosphonate treatment (25), and cell therapies (26).…”