Peripheral canalicular branching is decreased in streptozotocin-induced diabetes and correlates with decreased whole-bone ultimate load and perilacunar elastic work

Abstract

Osteocytes are the most abundant cell type in bone, important for mechanosensation, signaling for bone formation, resorption and osteocytes reside in a complex lacuno-canalicular network (OLCN). Osteocyte signaling is reduced under diabetic conditions, and both type 1 and type 2 diabetes lead to reduced bone turnover, perturbed bone composition and increased fracture risk. We hypothesized this reduced bone turnover and altered bone composition with diabetes is associated with reduced OLCN architecture and connectivity. This study aimed to elucidate: 1) the sequence of OLCN changes with diabetes related to bone turnover, and 2) whether changes to the OLCN are associated with tissue composition and mechanical properties. 12–14 week old male C57BL/6 mice were administered streptozotocin at 50 mg/kg for 5 consecutive days to induce hyperglycemia, sacrificed at baseline (BL), or after being diabetic for 3 (D3), 7 (D7) weeks with age-matched (C3, C7) controls (n = 10–12 per group). Mineralized femoral sections were infiltrated with rhodamine, imaged with confocal microscopy, then the OLCN morphology and topology were characterized and correlated against bone histomorphometry, local and whole bone mechanics and composition. D7 mice exhibited a lower number of peripheral branches relative to C7. The total number of canalicular intersections (nodes) was lower in D3 and D7 relative to BL (p < 0.05 for all) and a reduced bone formation rate (BFR) was observed at D7 vs. C7. The number of nodes explained only 15% of BFR, but 45% of Ct.BV/TV, and 31% of ultimate load. The number of branches explained 30% and 22% of the elastic work at the perilacunar and intracortical region, respectively. Collectively, the reduction in OLCN architecture, and association of OLCN measures with bone turnover, mechanics and composition highlights the relevance of the osteocyte and the OLCN, and a potential therapeutic target for treating diabetic skeletal fragility.