The Manganese-Bone Connection: Investigating the Role of Manganese in Bone Health

Abstract

The complex relationship between trace elements and skeletal health has received increasing attention in the scientific community. Among these minerals, manganese (Mn) has emerged as a key element affecting bone metabolism and integrity. This review examines the multifaceted role of Mn in bone health, including its effects on bone regeneration, mineralization, and overall skeletal strength. This review article is based on a synthesis of experimental models, epidemiologic studies, and clinical trials of the mechanisms of the effect of Mn on bone metabolism. Current research data show that Mn is actively involved in the processes of bone remodeling by modulating the activity of osteoblasts and osteoclasts, as well as the main cells that regulate bone formation and resorption. Mn ions have a profound effect on bone mineralization and density by intricately regulating signaling pathways and enzymatic reactions in these cells. Additionally, Mn superoxide dismutase (MnSOD), located in bone mitochondria, plays a crucial role in osteoclast differentiation and function, protecting osteoclasts from oxidative damage. Understanding the nuances of Mn's interaction with bone is essential for optimizing bone strategies, potentially preventing and managing skeletal diseases. Key findings include the stimulation of osteoblast proliferation and differentiation, the inhibition of osteoclastogenesis, and the preservation of bone mass through the RANK/RANKL/OPG pathway. These results underscore the importance of Mn in maintaining bone health and highlight the need for further research into its therapeutic potential.

Keywords: bone; bone health; bone mass; bone metabolism; manganese.

Figure 2

Manganese (Mn) superoxide dismutase (MnSOD) in the bone resorption [52]. RANKL-induced differentiation of macrophages into osteoclasts and the role of MnSOD in managing oxidative stress during bone resorption are depicted. RANKL binds to the RANK receptors on these cells, promoting their maturation. During bone resorption, superoxide (O₂⁻) is produced as a byproduct, and the mitochondrial enzyme MnSOD catalyzes the conversion of O₂⁻ into hydrogen peroxide (H₂O₂) and oxygen (O₂), thereby reducing oxidative stress. H₂O₂ is subsequently converted into water (H₂O), providing cellular protection. This process underscores the critical role of MnSOD in maintaining the functionality and integrity of osteoclasts during bone resorption.

Figure 3

Manganese (Mn) and bone remodeling [72]. The role of Mn in bone remodeling highlights its dual impact on osteoclasts and osteoblasts. Mn promotes osteoclast differentiation by enhancing the RANKL/RANK signaling pathway, where RANKL binds to RANK receptors on osteoclast progenitor cells, leading to their maturation into osteoclasts. Mature osteoclasts resorb bone, a process associated with oxidative stress, during which O₂⁻ is converted into less harmful molecules by the mitochondrial enzyme Mn superoxide dismutase (MnSOD). Concurrently, Mn inhibits the PI3K/AKT and WNT/β-catenin signaling pathways in mesenchymal stem cells (MSCs), thereby reducing the differentiation and activity of osteoblasts. This dual mechanism underscores the essential role of Mn in maintaining bone mass and integrity, ensuring effective bone regeneration and homeostasis by balancing bone resorption and formation.

Figure 1

The role of manganese (Mn) in bone cellular and molecular functions. The trace element Mn, with its various biochemical and physiological effects, participates in the synthesis of bone matrix, the inhibition of the formation of osteoclast-like cells, antioxidant function with the enzyme Mn superoxide dismutase (MnSOD), and mRNA expression of RANKL receptors; it also contributes to cell adhesion with extracellular matrix proteins, regulating osteoid formation. It also protects cartilage and stimulates chondrocyte growth through ZIP14. This is important for its integrin-activating functions, which contribute to the adhesion, integrity, and proliferation of osteoblasts.

Figure 4

Molecular mechanisms of manganese (Mn) metabolism. The molecular pathways involved in Mn metabolism highlight its absorption, transport, and accumulation in the body. Mn ions (Mn²⁺) are absorbed in the intestines through the divalent metal transporter 1 (DMT1). After absorption, Mn²⁺ ions enter the bloodstream and are transported in a complex with proteins. The liver, considered the central organ in Mn metabolism, plays a crucial role in processing and regulating Mn levels. Mn is then distributed from the liver to various tissues throughout the body, with a significant accumulation in the bones. This high accumulation in bones underscores the essential role of Mn in skeletal health.

Figure 5

Manganese (Mn) hemostasis in the bone [90]. The cellular mechanisms involved in maintaining Mn homeostasis in bones reveal the key physiological functions of Mn transporters and regulators, including ZIP8, ZNT10, and ZIP14. The process begins with the intake of Mn from food, where ZIP8 facilitates the intracellular accumulation of Mn²⁺ ions. These Mn²⁺ ions enter the bloodstream and are transported to various tissues, including bones and liver hepatocytes. The transport of Mn²⁺ ions into bones and other tissues is facilitated by the ubiquitously expressed ZIP14. Mn²⁺ ions reach the liver, where they undergo further processing and regulation. The ZIP10 transporter acts as an apical exporter, transporting Mn from the blood to the lumen of the small intestine for excretion in feces. These intricate regulatory mechanisms ensure the balance of Mn, which is crucial for maintaining bone health and overall metabolic homeostasis.