Cartilage Biology and Regenerative Medicine Laboratory, Section of Growth and Development, Division of Orthodontics, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032, USA.
Clemson University-Medical University of South Carolina Joint Bioengineering Program, Department of Bioengineering, Clemson University, Clemson, SC 29634, USA; Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Cell Stem Cell. 2023 Sep 7;30(9):1179-1198.e7. doi: 10.1016/j.stem.2023.08.004.
Osteoarthritis is a degenerative joint disease that causes pain, degradation, and dysfunction. Excessive canonical Wnt signaling in osteoarthritis contributes to chondrocyte phenotypic instability and loss of cartilage homeostasis; however, the regulatory niche is unknown. Using the temporomandibular joint as a model in multiple species, we identify Lgr5-expressing secretory cells as forming a Wnt inhibitory niche that instruct Wnt-inactive chondroprogenitors to form the nascent synovial joint and regulate chondrocyte lineage and identity. Lgr5 ablation or suppression during joint development, aging, or osteoarthritis results in depletion of Wnt-inactive chondroprogenitors and a surge of Wnt-activated, phenotypically unstable chondrocytes with osteoblast-like properties. We recapitulate the cartilage niche and create StemJEL, an injectable hydrogel therapy combining hyaluronic acid and sclerostin. Local delivery of StemJEL to post-traumatic osteoarthritic jaw and knee joints in rabbit, rat, and mini-pig models restores cartilage homeostasis, chondrocyte identity, and joint function. We provide proof of principal that StemJEL preserves the chondrocyte niche and alleviates osteoarthritis.
骨关节炎是一种退行性关节疾病，可引起疼痛、退化和功能障碍。骨关节炎中异常的经典 Wnt 信号会导致软骨细胞表型不稳定和软骨稳态丧失；然而，调控龛位尚不清楚。我们使用颞下颌关节作为多种物种的模型，发现 Lgr5 表达的分泌细胞形成了一个 Wnt 抑制龛位，指导 Wnt 非活跃的软骨祖细胞形成新生的滑膜关节，并调节软骨细胞谱系和特性。在关节发育、衰老或骨关节炎期间，Lgr5 的缺失或抑制会导致 Wnt 非活跃的软骨祖细胞耗竭，同时 Wnt 激活的、表型不稳定的具有成骨细胞样特性的软骨细胞激增。我们重现了软骨龛位，并创建了 StemJEL，这是一种将透明质酸和硬化素结合在一起的可注射水凝胶治疗方法。StemJEL 局部递送至兔、大鼠和小型猪创伤性骨关节炎颌骨和膝关节，可恢复软骨稳态、软骨细胞特性和关节功能。我们提供了主要证据表明 StemJEL 可保留软骨细胞龛位并缓解骨关节炎。
