Carnosine, Zinc and Copper: A Menage a Trois in Bone and Cartilage Protection

Abstract

Dysregulated metal homeostasis is associated with many pathological conditions, including arthritic diseases. Osteoarthritis and rheumatoid arthritis are the two most prevalent disorders that damage the joints and lead to cartilage and bone destruction. Recent studies show that the levels of zinc (Zn) and copper (Cu) are generally altered in the serum of arthritis patients. Therefore, metal dyshomeostasis may reflect the contribution of these trace elements to the disease's pathogenesis and manifestations, suggesting their potential for prognosis and treatment. Carnosine (Car) also emerged as a biomarker in arthritis and exerts protective and osteogenic effects in arthritic joints. Notably, its zinc(II) complex, polaprezinc, has been recently proposed as a drug-repurposing candidate for bone fracture healing. On these bases, this review article aims to provide an overview of the beneficial roles of Cu and Zn in bone and cartilage health and their potential application in tissue engineering. The effects of Car and polaprezinc in promoting cartilage and bone regeneration are also discussed. We hypothesize that polaprezinc could exchange Zn for Cu, present in the culture media, due to its higher sequestering ability towards Cu. However, future studies should unveil the potential contribution of Cu in the beneficial effects of polaprezinc.

Keywords: arthritis; bone; carnosine; cartilage; copper; zinc.

Figure 1

Comparison between healthy joints and OA and RA joints with the typical pathological alterations.

Figure 2

The putative linkage between inflammatory cytokines and increased Cu/Zn ratio in the serum of RA patients. Activation of T cells and macrophages leads to pro-inflammatory cytokines production, such as IL-1, IL-6, IL-17, and TNF-α. Cytokines induce fibroblasts to act as effectors of joint destruction through the release of other cytokines, chemokines, and proteases, like MMPs. Moreover, the pro-inflammatory cytokines stimulate the hepatic synthesis of CP, with consequent increased levels of Cu-CP in the blood. In addition, pro-inflammatory cytokines cause the overexpression of the Zn importer ZIP-14 in the liver. These effects lead to an increased Cu/Zn ratio in the serum of RA patients. The overall inflammatory state enhances ROS generation and oxidative stress, which in turn sustains inflammation and tissue injury. The symbols “↑” and “↓” stand for increase and reduction, respectively.

Figure 3

Simplified representation of the dynamic equilibrium between bone formation and resorption and the main signaling molecules involved.

Figure 4

Schematic illustration of carnosine synthesis and degradation. The acquamarine arrows define the type and source of the two amino acids.