Matrix modification for enhancing the transport properties of the human cartilage endplate to improve disc nutrition
Matrix modification for enhancing the transport properties of the human cartilage endplate to improve disc nutrition
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DOI：
10.1371/journal.pone.0215218
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发表时间：
2019-04-10
期刊：
影响因子：
3.7
通讯作者：
Fields, Aaron J.
中科院分区：
文献类型：
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作者：
Dolor, Aaron;Sampson, Sara L.;Fields, Aaron J.
通过软骨终板（CEP）的不良溶质转运损害椎间盘营养，可能是限制椎间盘内生物治疗成功的关键因素。在这里，我们表明，处理CEP与基质金属蛋白酶-8（MMP-8）减少了基质成分，阻碍溶质的吸收，从而提高营养扩散。用MMP-8处理从四个新鲜尸体腰椎（年龄范围：38-66岁）收获的人CEP组织。给药导致sGAG呈剂量依赖性降低，胶原蛋白量局部减少，胶原蛋白结构改变。这些基质修饰对应于小溶质（376 Da）摄取增加16-24%。有趣的是，MMP-8治疗的效果取决于非酶糖化的程度：与低浓度AGEs治疗的CEP相比，高浓度晚期糖基化终产物（AGEs）治疗的CEP摄取最低。此外，AGE浓度是供体特异性的，具有最高AGE浓度的供体组织似乎具有比基于胶原和sGAG的初始量预期的更低的摄取。最后，增加CEP中的溶质摄取改善了扩散室内的细胞活力，这支持了增强CEP的运输特性的营养相关性。综上所述，我们的研究结果提供了新的见解和体外概念验证的治疗方法，可以改善椎间盘营养的生物治疗：具体来说，基质减少MMP-8可以提高溶质的吸收和营养扩散通过CEP，AGE浓度似乎是一个重要的，患者特异性的因素，影响这种方法的疗效。
Poor solute transport through the cartilage endplate (CEP) impairs disc nutrition and could be a key factor that limits the success of intradiscal biologic therapies. Here we demonstrate that treating the CEP with matrix metalloproteinase-8 (MMP-8) reduces the matrix constituents that impede solute uptake and thereby improves nutrient diffusion. Human CEP tissues harvested from four fresh cadaveric lumbar spines (age range: 38-66 years old) were treated with MMP-8. Treatment caused a dose-dependent reduction in sGAG, localized reductions to the amount of collagen, and alterations to collagen structure. These matrix modifications corresponded with 16-24% increases in the uptake of a small solute (376 Da). Interestingly, the effects of MMP-8 treatment depended on the extent of non-enzymatic glycation: treated CEPs with high concentrations of advanced glycation end products (AGEs) exhibited the lowest uptake compared to treated CEPs with low concentrations of AGEs. Moreover, AGE concentrations were donor-specific, and the donor tissues with the highest AGE concentrations appeared to have lower uptake than would be expected based on the initial amounts of collagen and sGAG. Finally, increasing solute uptake in the CEP improved cell viability inside diffusion chambers, which supports the nutritional relevance of enhancing the transport properties of the CEP. Taken together, our results provide new insights and in vitro proof-of-concept for a treatment approach that could improve disc nutrition for biologic therapy: specifically, matrix reduction by MMP-8 can enhance solute uptake and nutrient diffusion through the CEP, and AGE concentration appears to be an important, patient-specific factor that influences the efficacy of this approach.