Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage critical for chondrocyte identity

作者：Angela Ruscitto, Peng Chen, Ikue Tosa, Ziyi Wang, Gan Zhou, Ingrid Safina, Ran Wei, Mallory M. Morel, Alia Koch, Michael Forman, Gwendolyn Reeve, Michael K. Lecholop, Marshall Wilson, Daniel J. Bonthius, Mo Chen, Mitsuaki Ono, Timothy C. Wang, Hai Yao, Mildred C. Embree · 发表于：Cell stem cell · 年份：2023 · DOI：10.1016/j.stem.2023.08.004 · 被引用次数：45 · 研究领域：Osteoarthritis Treatment and Mechanisms、Proteoglycans and glycosaminoglycans research、Cell Adhesion Molecules Research

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.