Bolger Morgan W, Tekkey Tara, Kohn David H
Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, MI 48109, United States.
Department of Chemistry, College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI 48109, United States.
JBMR Plus. 2024 Jan 4;8(3):ziad017. doi: 10.1093/jbmrpl/ziad017. eCollection 2024 Feb.
Osteocytes, the most abundant cell type in bone, play a crucial role in mechanosensation and signaling for bone formation and resorption. These cells reside within 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 that 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. Twelve- to fourteen-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) and 7 (D7) wk with age-matched (C3, C7) controls ( = 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, as well as 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 ( 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.
骨细胞是骨骼中最丰富的细胞类型，在骨形成和吸收的机械传感及信号传导中起关键作用。这些细胞位于复杂的骨陷窝-小管网络（OLCN）内。在糖尿病条件下，骨细胞信号传导会减弱，1型和2型糖尿病都会导致骨转换减少、骨成分紊乱以及骨折风险增加。我们推测，糖尿病导致的这种骨转换减少和骨成分改变与OLCN结构和连通性降低有关。本研究旨在阐明：（1）与骨转换相关的糖尿病患者OLCN变化的顺序，以及（2）OLCN的变化是否与组织成分和力学性能相关。给12至14周龄的雄性C57BL/6小鼠连续5天腹腔注射50mg/kg链脲佐菌素以诱导高血糖，在基线（BL）时处死，或在糖尿病3周（D3）和7周（D7）后处死，同时设置年龄匹配的（C3、C7）对照（每组n = 10 - 12）。用罗丹明浸润矿化的股骨切片，通过共聚焦显微镜成像，然后对OLCN的形态和拓扑结构进行表征，并与骨组织形态计量学、局部和全骨力学及成分进行相关性分析。与C7相比，D7小鼠的外周分支数量较少。与BL相比，D3和D7的小管交叉点（节点）总数较低（均P < 0.05），并且在D7时观察到与C7相比骨形成率（BFR）降低。节点数量仅解释了BFR的15%，但解释了骨小梁骨体积分数（Ct.BV/TV）的45%和极限载荷的31%。分支数量分别解释了骨陷窝周围和皮质内区域弹性功的30%和22%。总体而言，OLCN结构的减少以及OLCN测量值与骨转换、力学和成分的关联突出了骨细胞和OLCN的相关性以及治疗糖尿病性骨骼脆弱性的潜在治疗靶点。
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