Nell-1: A Potential Treatment for Inflammatory Arthritis

Objectives: Periodontal disease and tooth loss are more prevalent in people who have rheumatoid arthritis (RA), and it is broadly accepted that medical complications due to RA and its treatment can significantly affect oral health care. RA, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and inflammatory osteoarthritis are presenting inflammatory arthritis, for which the treatment directly targeting the biological causes is lacking. Our previous studies showed that Neural EGFL like 1 (Nell-1) suppresses BMP2-induced inflammation during bone regeneration and plays critical roles in cartilage development and regeneration. Here, we investigate the involvement and therapeutic potential of Nell-1 in inflammatory arthritis.
Methods: Immunostaining was conducted on human arthritic samples from patients undergoing hip or knee arthroplasty, and on mouse knee joints. A direct mouse intra-joint IL1β injection model was used to evaluate the efficacy of Nell-1 on inflammatory arthritis. The anti-inflammation effect of Nell-1 was further confirmed in both chondrogenic-committed ATDC5 cells and human chondrocytes.
Results: Inflammation in the human arthritic cartilage is accompanied by reduced Nell-1 expression. Nell-1 haploinsufficiency not only disrupts chondrogenic differentiation and maturation, but also leads to significant inflammation of cartilage in mice. Moreover, aged Nell-1^+/- mice exhibited more severe osteoarthritic alterations than wild-type (WT) controls. Moreover, IL1β challenging induced more severe inflammation and cartilage degradation of knee joint in Nell-1^+/- mice than in WT mice, while administration of exogenous Nell-1 significantly reduced the inflammatory response and articular cartilage damages. Excitingly, the lame walking observed in IL1β-challenged Nell-1^+/- mice were rescued by Nell-1 application. Similar anti-inflammation effects of Nell-1 were replicated in vitro, as evidenced by the strong repression of IL1β-induced inflammation in ATDC5 and in human chondrocytes.
Conclusions: Collectively, our present data revealed Nell-1 to be a pro-anabolic factor in the inflammation of arthritis and a potential arthritis-combating factor which will benefit oral health.