Park Sunghyun, Arai Yoshie, Bello Alvin, Park Hansoo, Kim Dohyun, Park Kyung-Soon, Lee Soo-Hong
Department Medical Biotechnology, Dongguk University Biomedi Campus, Goyang-si, Gyeonggi-do, Republic of Korea.
Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea.
NPJ Regen Med. 2021 Sep 17;6(1):56. doi: 10.1038/s41536-021-00165-9.
Osteoarthritis (OA) causes serious changes in the metabolic and signaling pathways of chondrocytes, including the mitogen-activated protein kinase (MAPK) pathway. However, the role of sprouty RTK signaling antagonist 4 (SPRY4), an inhibitor of MAPK, in the human cartilage tissues and chondrocytes remains to be understood. Here, using SPRY4 gene delivery into healthy and degenerated chondrocytes, we elucidated the role of SPRY4 in preventing chondrocyte hypertrophy. In addition to using the human cartilage tissues with the destabilization of the medial meniscus (DMM) model in Sprague-Dawley (SD) rats, the role of SPRY4 in cartilage tissues and chondrocytes was explored through their molecular and histological analyses. In order to determine the effects of SPRY4 on healthy human chondrocyte hypertrophy, small interfering RNA (siRNA) was used to knock down SPRY4. Lentiviral transduction of SPRY4 into degenerated human chondrocytes allowed us to investigate its ability to prevent hypertrophy. SPRY4 expression levels were higher in healthy human cartilage tissue and chondrocytes than in degenerated human cartilage tissues and hypertrophy-induced chondrocytes. The knockdown of SPRY4 in healthy chondrocytes caused an increase in hypertrophy, senescence, reactive oxygen species (ROS) production, and extracellular matrix (ECM) protease expression. However, all these factors decreased upon overexpression of SPRY4 in degenerated chondrocytes via regulation of the MAPK signaling pathway. We conclude that SPRY4 is a crucial indicator of osteoarthritis (OA) severity and could play an important role in preventing OA in the cartilage by inhibiting chondrocyte hypertrophy.
骨关节炎（OA）会导致软骨细胞的代谢和信号通路发生严重变化，包括丝裂原活化蛋白激酶（MAPK）通路。然而，作为MAPK抑制剂的Sprouty RTK信号拮抗剂4（SPRY4）在人软骨组织和软骨细胞中的作用仍有待明确。在此，我们通过将SPRY4基因导入健康和退变的软骨细胞，阐明了SPRY4在预防软骨细胞肥大中的作用。除了使用内侧半月板不稳定（DMM）模型的Sprague-Dawley（SD）大鼠的人软骨组织外，还通过分子和组织学分析探究了SPRY4在软骨组织和软骨细胞中的作用。为了确定SPRY4对健康人软骨细胞肥大的影响，使用小干扰RNA（siRNA）敲低SPRY4。将SPRY4慢病毒转导至退变的人软骨细胞中，使我们能够研究其预防肥大的能力。SPRY4在健康人软骨组织和软骨细胞中的表达水平高于退变的人软骨组织和肥大诱导的软骨细胞。在健康软骨细胞中敲低SPRY4会导致肥大、衰老、活性氧（ROS）产生和细胞外基质（ECM）蛋白酶表达增加。然而，通过调节MAPK信号通路，在退变软骨细胞中过表达SPRY4后，所有这些因素均降低。我们得出结论，SPRY4是骨关节炎（OA）严重程度的关键指标，并且通过抑制软骨细胞肥大在预防软骨OA中可能发挥重要作用。
