Department of Orthopedic Surgery, CAPHRI Care and Public Health Research Institute, Maastricht University Medical Center, Maastricht, the Netherlands.
Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
Cartilage. 2021 Jul;12(3):387-398. doi: 10.1177/1947603519833149. Epub 2019 Mar 17.
Despite the general awareness that cyclo-oxygenase-2 (COX-2) is crucial for endochondral ossification, the role of COX-2 in skeletal development is largely unknown. We hypothesized that inhibition or genetic loss of COX-2 leads to impaired growth plate development and consequently impaired postnatal development of the long bones.
Skeletally immature (5 weeks old) B6;129S-Ptgs2/J wildtype mice were treated for 10 weeks with celecoxib (daily oral administration 10 mg/kg) or placebo and compared with B6;129S-Ptgs2/J homozygous knockout mice ( = 12 per group).
Fifteen weeks postnatally, no significant difference in growth plate (zone) thickness was found between groups. However, significantly higher proteoglycan content and lower expression levels of collagen type II and X staining in the growth plates of celecoxib-treated mice, and to a lesser extent in COX-2 knockout mice. In addition, a significantly decreased cell number and cell size were observed in the hypertrophic zone of the growth plates of both experimental groups. Micro-computed tomography analysis of the subchondral bone region directly beneath the growth plate showed significantly higher bone density and trabecular thickness, following celecoxib treatment. Despite the detected differences in growth plate extracellular matrix composition and subchondral bone morphology, no difference was found in the length of the tibia in celecoxib-treated mice or COX-2 knockout mice.
Genetic loss of COX-2 or treatment with celecoxib did not result in detectable differences in gross murine formation of the tibia or femur. However, there were notable phenotypic features detected in the maturation of the growth plate (hypertrophic zone and subchondral bone) as a result of the celecoxib treatment.
尽管人们普遍认识到环氧化酶-2（COX-2）对于软骨内骨化至关重要，但 COX-2 在骨骼发育中的作用在很大程度上仍是未知的。我们假设 COX-2 的抑制或遗传缺失会导致生长板发育受损，进而导致长骨出生后发育受损。
对骨骼未成熟（5 周龄）的 B6;129S-Ptgs2/J 野生型小鼠用塞来昔布（每日口服 10mg/kg）或安慰剂治疗 10 周，并与 B6;129S-Ptgs2/J 纯合敲除小鼠（每组 = 12 只）进行比较。
出生后 15 周，各组生长板（区）厚度无显著差异。然而，塞来昔布治疗组的生长板中糖胺聚糖含量显著升高，Ⅱ型和 X 型胶原染色表达水平降低，而 COX-2 敲除组的程度较轻。此外，两组实验动物的生长板肥大区细胞数量和细胞体积均显著减少。生长板下软骨下骨区域的微计算机断层扫描分析显示，塞来昔布治疗后骨密度和小梁厚度显著增加。尽管生长板细胞外基质组成和软骨下骨形态存在差异，但塞来昔布治疗组或 COX-2 敲除组的胫骨长度没有差异。
COX-2 的遗传缺失或塞来昔布治疗并未导致小鼠胫骨或股骨的大体形态发生可检测的差异。然而，塞来昔布治疗后，生长板（肥大区和软骨下骨）的成熟出现了明显的表型特征。
