Osteoarthritis is a slowly progressive disease which includes the intervention of several cytokines, macrophage metalleinoproteinases reaction, leading to the degradation of the local cartilage but also having an impact on the serum acute phase proteins (APPs). Subsequently, biomarkers seem to be essential to estimate its progression and the need for any surgical intervention such as total arthroplasty, but also can be used as therapeutic agents. Recently, among APPs, fetuin A drew attention regarding its possible anti-inflammatory role in animal models but also as a therapeutic agent in the inflammatory joint disease in clinical trials. In contrast with other APPs such as C-reactive protein, fetuin A appears to be lower in the serum of patients with degenerative joint disease in comparison with the healthy ones, and also acts as an antagonist of the anti-proliferative potential of transforming growth factor-β (TGF-β) cytokines. Because of its lower serum levels in arthritis, an unregulated binding of TGF-β and bone morphogenetic proteins takes place leading to further arthritic lesions. The purpose of the present review is to assess the current evidence regarding the multipotent role of the alpha-2-HS-glycoprotein or as also known Fetuin-a in animal models but also as a biomarker of the degenerative joint arthritis in clinical trials.