Amelogenin Null Mice Develop Osteoarthritis, While Its Application Mitigates Disease Phenotypes in a Rat Model

Abstract

Previous studies have demonstrated that recombinant human amelogenin protein (rHAM⁺) promotes healing of injured articular cartilage, subchondral bone, and skeletal ligaments. Therefore, we speculated that amelogenin may play a role in osteoarthritis (OA) development. Aged amelogenin-null and wild-type mice underwent micro-computed tomography (micro-CT) and histological analyses to assess OA-related changes. Additionally, OA was induced in rat knees via destabilization of the medial meniscus, followed by treatment with 0.5 mg/mL rHAM⁺ dissolved in propylene glycol alginate (PGA) or PGA alone. Magnetic resonance imaging (MRI) and histological analyses were performed. Twenty-three-month-old amelogenin-null mice exhibited severe OA features, including cartilage loss, joint space narrowing, and osteophyte formation, whereas wild-type mice showed only mild, age-related changes. OA pathology was evident in 12-month-old amelogenin-null mice, by increased matrix metalloproteinase-13 (MMP-13) and decreased type II collagen expression. In osteoarthritic rats, MRI analyses demonstrated that treatment with rHAM⁺ delayed disease progression and improved OA phenotypes. Twenty-four weeks posttreatment, the levels of type II collagen increased, while MMP-13 and type X collagen decreased. MMP-13 reduction was detected as early as 2 weeks posttreatment, contributing to cartilage preservation. Furthermore, similar to the known effect of rHAM⁺ in acute injuries, recruitment of CD105-positive mesenchymal stem cells to the cartilage was detected 5 days posttreatment. Lack of amelogenin led to the development of osteoarthritic phenotypes, whereas in the induced osteoarthritis model, a single application of amelogenin inhibited joint deterioration and partially healed osteoarthritic damage compared with the control. These findings highlight the potential of amelogenin as a disease-modifying agent for OA.