Aggrecan Hypomorphism Compromises Articular Cartilage Biomechanical Properties and Is Associated with Increased Incidence of Spontaneous Osteoarthritis
Aggrecan Hypomorphism Compromises Articular Cartilage Biomechanical Properties and Is Associated with Increased Incidence of Spontaneous Osteoarthritis
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DOI：
10.3390/ijms20051008
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发表时间：
2019-03-01
影响因子：
5.6
通讯作者：
Aszodi, Attila
中科院分区：
文献类型：
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作者：
Alberton, Paolo;Dugonitsch, Hans Christian;Aszodi, Attila
蛋白多糖聚集素(Agc1)基因在软骨发育和成年期大量表达，蛋白丢失或沉积减少会导致多种骨骼畸形。此外，聚集素的降解是骨关节炎软骨退变的一个标志。在这项研究中，我们研究了聚集素在出生后骨骼和成年小鼠关节软骨中部分丢失的后果。我们利用了前面描述的Agc1(tm(IRES-CreERT2))小鼠系，它允许有条件的和及时调节的删除软骨表达的基因。正如以前报道的那样，在3‘非编码区中引入Creer(T2)盒会导致Agc1的正常表达中断，导致蛋白质的亚型沉积。在纯合子小鼠中，我们观察到一种矮小的表型，这种表型在整个成年期持续存在，支持了聚集素含量减少会损害骨骼生长的证据。纯合子小鼠在6个月和12个月龄时关节软骨蛋白多糖染色减少，6个月时细胞外基质硬化增加，12个月后出现严重的软骨侵蚀。畸形低下小鼠的骨性关节炎并不伴随分解代谢酶和基质降解新表位的表达增加。这些发现表明，在纯合子小鼠中发现的退化可能是由于聚集素减少时软骨组织的机械性能受损所致。
The gene encoding the proteoglycan aggrecan (Agc1) is abundantly expressed in cartilage during development and adulthood, and the loss or diminished deposition of the protein results in a wide range of skeletal malformations. Furthermore, aggrecan degradation is a hallmark of cartilage degeneration occurring in osteoarthritis. In the present study, we investigated the consequences of a partial loss of aggrecan in the postnatal skeleton and in the articular cartilage of adult mice. We took advantage of the previously described Agc1(tm(IRES-CreERT2)) mouse line, which allows for conditional and timely-regulated deletion of floxed, cartilage-expressed genes. As previously reported, the introduction of the CreER(T2) cassette in the 3'UTR causes a disruption of the normal expression of Agc1 resulting in a hypomorphic deposition of the protein. In homozygous mice, we observed a dwarf phenotype, which persisted throughout adulthood supporting the evidence that reduced aggrecan amount impairs skeletal growth. Homozygous mice exhibited reduced proteoglycan staining of the articular cartilage at 6 and 12 months of age, increased stiffening of the extracellular matrix at six months, and developed severe cartilage erosion by 12 months. The osteoarthritis in the hypomorph mice was not accompanied by increased expression of catabolic enzymes and matrix degradation neoepitopes. These findings suggest that the degeneration found in homozygous mice is likely due to the compromised mechanical properties of the cartilage tissue upon aggrecan reduction.