Boneski Paige K, Madhu Vedavathi, Tomlinson Ryan E, Shapiro Irving M, van de Wetering Koen, Risbud Makarand V
Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA, United States.
Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States.
Front Cell Dev Biol. 2022 Feb 3;10:823249. doi: 10.3389/fcell.2022.823249. eCollection 2022.
Chronic low back pain is a highly prevalent health condition intricately linked to intervertebral disc degeneration. One of the prominent features of disc degeneration that is commonly observed with aging is dystrophic calcification. ATP-binding cassette sub-family C member 6 (ABCC6), a presumed ATP efflux transporter, is a key regulator of systemic levels of the mineralization inhibitor pyrophosphate (PPi). Mutations in ABCC6 result in pseudoxanthoma elasticum (PXE), a progressive human metabolic disorder characterized by mineralization of the skin and elastic tissues. The implications of ABCC6 loss-of-function on pathological mineralization of structures in the spine, however, are unknown. Using the mouse model of PXE, we investigated age-dependent changes in the vertebral bone and intervertebral disc. mice exhibited diminished trabecular bone quality parameters at 7 months, which remained significantly lower than the wild-type mice at 18 months of age. vertebrae showed increased TRAP staining along with decreased TNAP staining, suggesting an enhanced bone resorption as well as decreased bone formation. Surprisingly, however, loss of ABCC6 resulted only in a mild, aging disc phenotype without evidence of dystrophic mineralization. Finally, we tested the utility of oral K3Citrate to treat the vertebral phenotype since it is shown to regulate hydroxyapatite mechanical behavior. The treatment resulted in inhibition of the osteoclastic response and an early improvement in mechanical properties of the bone underscoring the promise of potassium citrate as a therapeutic agent. Our data suggest that although ectopic mineralization is tightly regulated in the disc, loss of ABCC6 compromises vertebral bone quality and dysregulates osteoblast-osteoclast coupling.
慢性下腰痛是一种与椎间盘退变密切相关的高度普遍的健康状况。随着年龄增长，椎间盘退变的一个显著特征是营养不良性钙化。ATP结合盒亚家族C成员6（ABCC6），一种推测的ATP外排转运蛋白，是矿化抑制剂焦磷酸（PPi）全身水平的关键调节因子。ABCC6基因突变导致弹性假黄瘤（PXE），这是一种进行性人类代谢紊乱疾病，其特征是皮肤和弹性组织矿化。然而，ABCC6功能丧失对脊柱结构病理性矿化的影响尚不清楚。利用PXE小鼠模型，我们研究了椎骨和椎间盘的年龄依赖性变化。PXE小鼠在7个月时小梁骨质量参数降低，在18个月龄时仍显著低于野生型小鼠。PXE椎骨显示TRAP染色增加，同时TNAP染色减少，表明骨吸收增强以及骨形成减少。然而，令人惊讶的是，ABCC6的缺失仅导致轻度的、类似衰老的椎间盘表型，没有营养不良性矿化的证据。最后，我们测试了口服柠檬酸钾治疗椎体表型的效用，因为它已被证明可调节羟基磷灰石的力学行为。该治疗导致破骨细胞反应受到抑制，并且骨力学性能早期得到改善，突出了柠檬酸钾作为治疗剂的前景。我们的数据表明，尽管椎间盘异位矿化受到严格调控，但ABCC6的缺失会损害椎骨质量并使成骨细胞 - 破骨细胞偶联失调。
