Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss
Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss
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DOI：
10.1038/s41598-020-71749-6
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发表时间：
2020-09-09
影响因子：
4.6
通讯作者：
Niederreither, Karen
中科院分区：
文献类型：
--
作者：
Morkmued, Supawich;Clauss, Francois;Niederreither, Karen
调节颅面发育的分泌性细胞外基质成分可以被重新激活，并在成人伤口愈合中发挥作用。我们报告一个病人的功能丧失的分泌基质细胞蛋白SMOC2（骨相关模块钙结合2）提出严重的少牙，小牙，牙根缺陷，牙槽骨发育不全，和一系列的骨骼畸形。转向小鼠模型，Smoc 2-GFP报告基因表达表明SMOC 2动态标记一系列牙齿和骨祖细胞。虽然种系Smoc 2纯合突变体是可行的，但在该小鼠模型中观察到牙齿数量异常、牙齿尺寸减小、釉质棱柱图案改变以及自发的年龄诱导的牙周骨和牙根缺失。对胚胎第14.5天帽状期磨牙的全基因组RNA测序分析显示，早期表达的釉质基质成分（牙源性成釉细胞相关蛋白）和牙本质发育不良靶点（牙本质基质酸性磷蛋白1）减少。我们测试了SMOC2是否像其他基质细胞蛋白一样是再生修复所必需的。我们发现Smoc2-GFP报告基因在牙齿撕脱伤后4天在邻近的牙周组织中被重新激活。上颌牙损伤后，Smoc 2（-/-）突变体增加破骨细胞活性和骨吸收周围提取的磨牙。有趣的是，10天的治疗与环氧合酶2（COX2）抑制剂布洛芬（30毫克/公斤体重）阻止Smoc 2（-/-）突变体的牙齿损伤诱导的骨丢失，减少基质金属蛋白酶（Mmp）9。总的来说，我们的研究结果表明，内源性SMOC2阻断损伤引起的颌骨骨坏死和抵消年龄引起的牙周衰变。
Secreted extracellular matrix components which regulate craniofacial development could be reactivated and play roles in adult wound healing. We report a patient with a loss-of-function of the secreted matricellular protein SMOC2 (SPARC related modular calcium binding 2) presenting severe oligodontia, microdontia, tooth root deficiencies, alveolar bone hypoplasia, and a range of skeletal malformations. Turning to a mouse model, Smoc2-GFP reporter expression indicates SMOC2 dynamically marks a range of dental and bone progenitors. While germline Smoc2 homozygous mutants are viable, tooth number anomalies, reduced tooth size, altered enamel prism patterning, and spontaneous age-induced periodontal bone and root loss are observed in this mouse model. Whole-genome RNA-sequencing analysis of embryonic day (E) 14.5 cap stage molars revealed reductions in early expressed enamel matrix components (Odontogenic ameloblast-associated protein) and dentin dysplasia targets (Dentin matrix acidic phosphoprotein 1). We tested if like other matricellular proteins SMOC2 was required for regenerative repair. We found that the Smoc2-GFP reporter was reactivated in adjacent periodontal tissues 4 days after tooth avulsion injury. Following maxillary tooth injury, Smoc2(-/-) mutants had increased osteoclast activity and bone resorption surrounding the extracted molar. Interestingly, a 10-day treatment with the cyclooxygenase 2 (COX2) inhibitor ibuprofen (30 mg/kg body weight) blocked tooth injury-induced bone loss in Smoc2(-/-) mutants, reducing matrix metalloprotease (Mmp)9. Collectively, our results indicate that endogenous SMOC2 blocks injury-induced jaw bone osteonecrosis and offsets age-induced periodontal decay.