Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage critical for chondrocyte identity.
Angela RuscittoPeng ChenIkue TosaZiyi WangGan ZhouIngrid SafinaRan WeiMallory M MorelAlia KochMichael FormanGwendolyn ReeveMichael K LecholopMarshall WilsonDaniel BonthiusMo ChenMitsuaki OnoTimothy C WangHai YaoMildred C EmbreePublished in: Cell stem cell (2023)
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.
Keyphrases
- hyaluronic acid
- cell proliferation
- stem cells
- knee osteoarthritis
- induced apoptosis
- rheumatoid arthritis
- extracellular matrix
- cell cycle arrest
- oxidative stress
- drug delivery
- total knee arthroplasty
- transcription factor
- endoplasmic reticulum stress
- physical activity
- spinal cord injury
- body mass index
- radiofrequency ablation
- neuropathic pain
- mouse model
- bone marrow
- cell therapy
- postoperative pain
- replacement therapy