Material properties of bighorn sheep (Ovis canadensis) horncore bone with implications for energy absorption during impacts

AUTHORS

Luca H.Fuller, Seth W.Donahue

ABSTRACT

Bighorn sheep rams participate in high impact head-butting without overt signs of brain injury, thus providing a naturally occurring animal model for studying brain injury mitigation. Previously published finite element modeling showed that both the horn and bone materials play important roles in reducing brain cavity accelerations during ramming. However, in that study the elastic modulus of bone was assumed to be similar to that of human bone since the modulus of ram bone was unknown. Therefore, the goal of this study was to quantify the mechanical properties, mineral content, porosity, and microstructural organization of horncore cortical bone from juvenile and adult rams. Mineral content and elastic modulus increased with horn size, and porosity decreased. However, modulus of toughness did not change with horn size. This latter finding raises the possibility that the horncore cortical bone has not adapted exceptional toughness despite an extreme loading environment and may function primarily as an interface material between the horn and the porous bone within the horncore. Thus, geometric properties of the horn and horncore, including the porous bone architecture, may be more important for energy absorption during ramming than the horncore cortical bone. Results from this study can be used to improve accuracy of finite element models of bighorn sheep ramming to investigate these possibilities moving forward.

Ferroptosis Mediates Cuprizone-Induced Loss of Oligodendrocytes and Demyelination

AUTHORS

Priya Jhelum, Eva Santos-Nogueira, Wulin Teo, Alice Haumont, Isadora Lenoël, Peter K. Stys and Samuel David

ABSTRACT

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Cuprizone (CZ), a copper chelator, is widely used to study demyelination and remyelination in the CNS, in the context of MS. However, the mechanisms underlying oligodendrocyte (OL) cell loss and demyelination are not known. As copper-containing enzymes play important roles in iron homeostasis and controlling oxidative stress, we examined whether chelating copper leads to disruption of molecules involved in iron homeostasis that can trigger iron-mediated OL loss. We show that giving mice (male) CZ in the diet induces rapid loss of OL in the corpus callosum by 2 d, accompanied by expression of several markers for ferroptosis, a relatively newly described form of iron-mediated cell death. In ferroptosis, iron-mediated free radicals trigger lipid peroxidation under conditions of glutathione insufficiency, and a reduced capacity to repair lipid damage. This was further confirmed using a small-molecule inhibitor of ferroptosis that prevents CZ-induced loss of OL and demyelination, providing clear evidence of a copper-iron connection in CZ-induced neurotoxicity. This work has wider implications for disorders, such as multiple sclerosis and CNS injury.

Ablation of Enpp6 Results in Transient Bone Hypomineralization

AUTHORS

Scott Dillon, Karla Suchacki, Shun-Neng Hsu, Louise A Stephen, Rongling Wang, William P Cawthorn, Alan J Stewart, Fabio Nudelman, Nicholas M Morton, Colin Farquharson

ABSTRACT

Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. However, the biochemical pathways that generate intravesicular PHOSPHO1 substrates are currently unknown. We hypothesized that the enzyme ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6) is an upstream source of the PHOSPHO1 substrate. To test this, we characterized skeletal phenotypes of mice homozygous for a targeted deletion of Enpp6 (Enpp6−/−). Micro-computed tomography of the trabecular compartment revealed transient hypomineralization in Enpp6−/− tibias (p < 0.05) that normalized by 12 weeks of age. Whole-bone cortical analysis also revealed significantly hypomineralized proximal bone in 4- but not 12-week-old Enpp6−/− mice (p < 0.05) compared with WT animals. Back-scattered SEM revealed a failure in 4-week-old trabecular bone of mineralization foci to propagate. Static histomorphometry revealed increased osteoid volume (p > 0.01) and osteoid surface (p < 0.05), which recovered by 12 weeks but was not accompanied by changes in osteoblast or osteoclast number. This study is the first to characterize the skeletal phenotype of Enpp6−/− mice, revealing transient hypomineralization in young animals compared with WT controls. These data suggest that ENPP6 is important for bone mineralization and may function upstream of PHOSPHO1 as a novel means of generating its substrates inside matrix vesicles.