Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
J Bone Miner Res. 2018 Sep;33(9):1708-1717. doi: 10.1002/jbmr.3441. Epub 2018 Jun 13.
Bone morphogenetic proteins (BMPs) are key regulators of skeletal development, growth, and repair. Although BMP signaling is required for synovial joint formation and is also involved in preserving joint function after birth, the role of specific BMP ligands in adult joint homeostasis remains unclear. The purpose of this study was to define the role of Bmp2 in the morphogenesis and maintenance of the knee joint. To do this, we first created Bmp2-LacZ and Gdf5-LacZ knock-in mice and compared their expression patterns in the developing and postnatal murine knee joint. We then generated a knockout mouse model using the Gdf5-cre transgene to specifically delete Bmp2 within synovial joint-forming cells. Joint formation, maturation, and homeostasis were analyzed using histology, immunohistochemistry, qRT-PCR, and atomic force microscopy (AFM)-based nanoindentation to assess the cellular, molecular, and biomechanical changes in meniscus and articular cartilage. Bmp2 is expressed in the articular cartilage and meniscus of the embryonic and adult mouse knee in a pattern distinct from Gdf5. The knee joints of the Bmp2 knockout mice form normally but fail to mature properly. In the absence of Bmp2, the extracellular matrix and shape of the meniscus are altered, resulting in functional deficits in the meniscus and articular cartilage that lead to a progressive osteoarthritis (OA) like knee pathology as the animals age. These findings demonstrate that BMP activity provided by Bmp2 is required for the maturation and maintenance of the murine knee joint and reveal a unique role for Bmp2 that is distinct from Gdf5 in knee joint biology. © 2018 American Society for Bone and Mineral Research.
骨形态发生蛋白（BMPs）是骨骼发育、生长和修复的关键调节因子。尽管 BMP 信号对于滑膜关节的形成是必需的，并且在出生后也参与维持关节功能，但特定 BMP 配体在成人关节稳态中的作用仍不清楚。本研究的目的是确定 Bmp2 在膝关节形态发生和维持中的作用。为此，我们首先创建了 Bmp2-LacZ 和 Gdf5-LacZ 基因敲入小鼠，并比较了它们在发育中和出生后鼠膝关节中的表达模式。然后，我们使用 Gdf5-cre 转基因生成了一种敲除小鼠模型，以特异性删除滑膜关节形成细胞中的 Bmp2。使用组织学、免疫组织化学、qRT-PCR 和原子力显微镜（AFM）-基于纳米压痕来评估半月板和关节软骨中的细胞、分子和生物力学变化，以分析关节形成、成熟和稳态。Bmp2 在胚胎期和成年期小鼠膝关节的关节软骨和半月板中的表达模式与 Gdf5 不同。Bmp2 敲除小鼠的膝关节正常形成，但不能正常成熟。在没有 Bmp2 的情况下，半月板的细胞外基质和形状发生改变，导致半月板和关节软骨的功能缺陷，导致随着动物年龄的增长出现进行性骨关节炎（OA）样膝关节病变。这些发现表明，Bmp2 提供的 BMP 活性对于鼠膝关节的成熟和维持是必需的，并揭示了 Bmp2 在膝关节生物学中与 Gdf5 不同的独特作用。© 2018 美国骨矿研究协会。
