Back pain is a common condition with a high social impact and represents a global health burden. Intervertebral disc disease (IVDD) is one of the major causes of back pain; no therapeutics are currently available to reverse this disease. The impact of bone mineral density (BMD) on IVDD has been controversial, with some studies suggesting osteoporosis as causative for IVDD and others suggesting it as protective for IVDD. Functional studies to evaluate the influence of genetic components of BMD in IVDD could highlight opportunities for drug development and repurposing. By taking a holistic 3D approach, we established an aging zebrafish model for spontaneous IVDD. Increased BMD in aging, detected by automated computational analysis, is caused by bone deformities at the endplates. However, aged zebrafish spines showed changes in bone morphology, microstructure, mineral heterogeneity, and increased fragility that resembled osteoporosis. Elements of the discs recapitulated IVDD symptoms found in humans: the intervertebral ligament (equivalent to the annulus fibrosus) showed disorganized collagen fibers and herniation, while the disc center (nucleus pulposus equivalent) showed dehydration and cellular abnormalities. We manipulated BMD in young zebrafish by mutating sp7 and cathepsin K, leading to low and high BMD, respectively. Remarkably, we detected IVDD in both groups, demonstrating that low BMD does not protect against IVDD, and we found a strong correlation between high BMD and IVDD. Deep learning was applied to high-resolution synchrotron µCT image data to analyze osteocyte 3D lacunar distribution and morphology, revealing a role of sp7 in controlling the osteocyte lacunar 3D profile. Our findings suggest potential avenues through which bone quality can be targeted to identify beneficial therapeutics for IVDD.

背痛是一种具有高度社会影响的常见疾病，是全球健康负担。椎间盘疾病 (IVDD) 是背痛的主要原因之一；目前没有治疗方法可以逆转这种疾病。骨矿物质密度 (BMD) 对 IVDD 的影响一直存在争议，一些研究表明骨质疏松症是 IVDD 的原因，而另一些研究表明它对 IVDD 具有保护作用。评估 IVDD 中 BMD 遗传成分影响的功能研究可以突出药物开发和再利用的机会。通过采用整体 3D 方法，我们为自发性 IVDD 建立了老化斑马鱼模型。通过自动计算分析检测到的老化 BMD 增加是由终板的骨骼畸形引起的。然而，老化的斑马鱼刺显示出骨骼形态的变化，微观结构、矿物质异质性和增加的类似于骨质疏松症的脆性。椎间盘的元素概括了人类发现的 IVDD 症状：椎间韧带（相当于纤维环）显示出胶原纤维紊乱和突出，而椎间盘中心（相当于髓核）显示脱水和细胞异常。我们通过变异来操纵年轻斑马鱼的 BMDsp7和组织蛋白酶 K，分别导致低和高 BMD。值得注意的是，我们在两组中都检测到 IVDD，表明低 BMD 并不能防止 IVDD，我们发现高 BMD 和 IVDD 之间存在很强的相关性。深度学习应用于高分辨率同步加速器 μCT 图像数据以分析骨细胞 3D 腔隙分布和形态，揭示sp7在控制骨细胞腔隙 3D 轮廓中的作用。我们的研究结果提出了潜在的途径，通过这些途径可以针对骨质量来确定 IVDD 的有益疗法。