Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model.
Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model.
复制标题
DOI：
10.1002/art.39508
复制
发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Pitsillides AA
中科院分区：
文献类型：
--
作者：
Staines KA;Madi K;Mirczuk SM;Parker S;Burleigh A;Poulet B;Hopkinson M;Bodey AJ;Fowkes RC;Farquharson C;Lee PD;Pitsillides AA
探索STR/Ort小鼠（自发性发生骨关节炎[OA]）关节中是否发生异常的瞬时软骨细胞行为，以及它们是否可归因于软骨内生长缺陷。通过Affyphin微阵列分析、多重聚合酶链反应（PCR）分析和软骨内标志物（包括硬化蛋白和MEPE）的免疫组织化学标记，检查了患有晚期OA的STR/Ort小鼠和年龄匹配的CBA（对照）小鼠的膝关节。通过组织学检查、显微计算机断层扫描和离体器官培养分析STR/Ort小鼠的内软骨表型。开发并应用了一种使用同步加速器X射线计算机显微断层扫描定量小鼠骨骺（生长板融合）骨桥的新方案。转录谱的Meta分析显示，STR/Ort小鼠中与软骨内骨化相关的功能显著升高（与CBA小鼠相比; P < 0.05）。与此一致，免疫标记显示STR/Ort小鼠关节中基质金属蛋白酶13（MMP-13）和X型胶原表达增加，多重定量逆转录酶-PCR显示已知矿化调节剂的差异表达，表明固有的软骨细胞缺陷。支持软骨内缺陷概念的因素包括生长加速、生长板增殖软骨细胞区增加（P < 0.05）以及X型胶原/MMP-13标记超出预期肥大区分布。OA发展涉及STR/Ort小鼠中硬化蛋白/MEPE的伴随局灶性抑制。我们的新型同步辐射显微断层扫描方法显示，与年龄匹配的CBA小鼠相比，年轻和老年STR/Ort小鼠的数量（P < 0.001）和平均区域生长板桥密度（P < 0.01）增加。综上所述，我们的数据支持固有的软骨内分泌缺陷的概念，其与生长动力学相关，并受MEPE/sclerostin轴的调节，可能代表OA病理性骨化的潜在机制。
To explore whether aberrant transient chondrocyte behaviors occur in the joints of STR/Ort mice (which spontaneously develop osteoarthritis [OA]) and whether they are attributable to an endochondral growth defect. Knee joints from STR/Ort mice with advanced OA and age‐matched CBA (control) mice were examined by Affymetrix microarray profiling, multiplex polymerase chain reaction (PCR) analysis, and immunohistochemical labeling of endochondral markers, including sclerostin and MEPE. The endochondral phenotype of STR/Ort mice was analyzed by histologic examination, micro–computed tomography, and ex vivo organ culture. A novel protocol for quantifying bony bridges across the murine epiphysis (growth plate fusion) using synchrotron x‐ray computed microtomography was developed and applied. Meta‐analysis of transcription profiles showed significant elevation in functions linked with endochondral ossification in STR/Ort mice (compared to CBA mice; P < 0.05). Consistent with this, immunolabeling revealed increased matrix metalloproteinase 13 (MMP‐13) and type X collagen expression in STR/Ort mouse joints, and multiplex quantitative reverse transcriptase–PCR showed differential expression of known mineralization regulators, suggesting an inherent chondrocyte defect. Support for the notion of an endochondral defect included accelerated growth, increased zone of growth plate proliferative chondrocytes (P < 0.05), and widespread type X collagen/MMP‐13 labeling beyond the expected hypertrophic zone distribution. OA development involved concomitant focal suppression of sclerostin/MEPE in STR/Ort mice. Our novel synchrotron radiation microtomography method showed increased numbers (P < 0.001) and mean areal growth plate bridge densities (P < 0.01) in young and aged STR/Ort mice compared to age‐matched CBA mice. Taken together, our data support the notion of an inherent endochondral defect that is linked to growth dynamics and subject to regulation by the MEPE/sclerostin axis and may represent an underlying mechanism of pathologic ossification in OA.