Bone remodeling is a lifelong process wherein old bone is removed from the skeleton by bone resorption and replaced with new bone by bone formation. The bone remodeling unit comprises the osteoclast (OC), osteoblast (OB), and osteocytes. The bone remodeling process can be divided into six phases: quiescent, activation, resorption, reversal, formation, and mineralization [21]. In normal conditions, the length of the bone remodeling process is about 200 days, and the remodeling cycle is longer in cancellous bone than in cortical bone. The duration of bone remodeling is shortened in hyperthyroidism and hyperparathyroidism, and it is longer in low bone turnover diseases like adynamic bone disease or osteomalacia [22].

Osteoblastic cells regulate osteoclast differentiation and activation through receptor activator of nuclear factor kappa-Β ligand (RANKL)-mediated signaling pathways. RANKL expressed in osteoblasts can be induced by 1,25 vitamin D, parathyroid hormone (PTH), and IL-6. The RANKL receptor is called RANK and is expressed in osteoclast progenitors to promote osteoclast differentiation and maturation. Macrophage colony-stimulating factor (M-CSF) is another important element to promote osteoclast proliferation and differentiation, and it is constitutively expressed in osteoblasts. Osteoprotegerin (OPG) is an inhibitory factor that inhibits osteoclast differentiation and activation by interfering with the binding of RANKL to RANK [23].

There is increasing evidence to support the important role of ephrin and ephrin receptor (Eph) bi-directional signaling in normal bone coupling of bone resorption to bone formation [24]. Cells in the osteoclast lineage produce various coupling stimulators and inhibitors during the bone resorption process, which act on osteoblasts or their progenitors. The bone matrix also secretes transforming growth factor β (TGF-β) and insulin-like growth factor-I (IGF-I) during osteoclastic bone resorption and, subsequently, activates osteoblast bone formation. Several other coupling factors, such as semaphorin 4D, cardiotrophin-1, sphingosine-1-phosphate, bone morphogenetic protein 6, and Wnt 10b, have also been identified in bone unit communication [25].

Several possible mechanisms of osteoporosis have been proposed, including:

(a) Increased inflammatory cytokine-associated osteolysis. It leads to excessive activity of osteoclasts and leads to more bone resorption than bone formation. This phenomenon can be seen in gouty arthritis, inflammation, and vitamin D deficiency [26].

(b) Incoordination of the RANK/RANKL system. Increased RANK/RANKL signal in OC strengthens the performance of osteoclasts and brings about more bone resorption. There are many clinical scenarios such as in hyperparathyroidism and some autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and estrogen deprivation (postmenopausal women) ^[26][27][26,27].

(c) Excessive Wnt signaling inhibitors in osteoblasts. Dickkopf-1, sclerostin, and secreted frizzled related proteins lead to diminished functioning of osteoblasts via a decrease in Wnt signaling activity, then reduced bone formation. This has been proven in chronic kidney disease, glucocorticoid-induced osteoporosis, and vascular calcification-related bone loss [28].

In human plasma, circulating UA acts as an antioxidant in several mechanisms (Figure 1). UA reacts with different oxidants including superoxide anions, hydrogen radicals, and, at the highest affinity, peroxynitrite. Peroxynitrite is a potent oxidant, generated by the rapid combination of free radical nitric oxide (NO) and superoxide, which can induce the inflammation response, lipid peroxidation, and tyrosine nitration ^[29][30][29,30]. Peroxynitrite also acts as an oxidant of tetrahydrobiopterin and leads to the uncoupling of nitric oxide synthase (NOS) [31]. Hence, peroxynitrite can increase superoxide and decrease NO production by eNOS uncoupling, and UA has protective effects against it. Besides, UA is an effective scavenger for peroxyl radicals (ROO⁻). Compared to ascorbic acid, UA is the major important water-soluble antioxidant in human plasma. Plasma UA levels are higher than plasma ascorbic acid levels, and UA has a higher reduction potential that leads to less iron and copper production, which is important for the Fenton reaction and hydroxyl radical generation ^[32][33][32,33]. Additionally, UA is an iron chelator to reduce iron-catalyzed oxidative stress reaction ^[34][35][36][34,35,36]. UA at physiologic concentrations has the ability to scavenge reactive oxygen species (ROS) and protect the erythrocyte membrane from lipid oxidation and further hemolysis [37]. Acute elevation of UA has a protective effect on cultured hippocampal neurons after ischemic insult and suppress the accumulation of reactive oxygen species after excitotoxic and metabolic insults [38]. Moreover, administration of UA can significantly attenuate the formation of nitrotyrosine in liver injury by hemorrhagic shock [39]. At the same time, UA can reduce neutrophil infiltration, which suggests that UA can prevent proinflammatory cell activation by oxidant stress [39]. Treatment with UA at a physiologic dose led to greater functional performance of the heart damaged by radicals and oxidants [40].

As shown in Figure 1, xanthine oxidase (XO) is the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and of xanthine to UA, and there are two superoxide radicals produced during this process. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase 4; NOX4) belongs to the NOX catalytic enzyme family that generates ROS. NADPH oxidase is located on the cell membrane and functions in intracellular electron transfer across the cell membrane, which converts extracellular molecular oxygen into superoxide radicals. Extracellular superoxide can dismutate to hydrogen peroxide. Both extracellular superoxide radicals and hydrogen peroxide can penetrate the cell membrane through chloride channel-3 (ClC3) and aquaporin channels, respectively, and subsequently initiate intracellular signaling and oxidative stress ^[41][42][41,42].

In addition, free radicals are produced during the process of UA degradation inside the cell. For example, an unpaired electron of the urate anion free radical is located on the five-membered ring of purine [43], and a carbon-centered free radical forms during the reaction of peroxynitrite to purine [31]. The reaction between UA and peroxynitrite is on a second-order rate and needs to consume oxygen. The final products of urate and peroxynitrite are allantoin, alloxan, and aminocarbonyl radicals. Allantoin and alloxan are produced during urate oxidation by other oxidants, whereas the aminocarbonyl radical is produced by peroxynitrite oxidation [44]. At physiological concentrations of UA, around 0.5 nM in human plasma, UA can increase the oxidation of liposomes and LDL promoted by the peroxynitrite-attacked end product, especially the aminocarbonyl radical [44]. It is worth to note that UA can react with peroxynitrite to produce radicals, and these radicals can further react with peroxynitrite to produce radicals in chain reaction. Furthermore, the antioxidant property of extracellular uric acid would be hindered by the hydrophobic conditions created by the lipid layer of the cell membrane, and oxidized lipids can convert uric acid into an oxidant with the help of copper ^[45][46][45,46]. The shift of UA between oxidant and antioxidant is related to the availability of lipid hydroperoxides formed during the early phase of LDL oxidation [46]. In differentiated mouse adipocytes and human subcutaneous primary adipocytes, UA significantly increases ROS production [47]. UA can also increase NAPHD oxidase activity directly and enhance intracellular superoxide generation. Production of peroxynitrite contributes to an inflammatory response that damages tissues by inducing lipid peroxidation. Both superoxide and peroxynitrite induce osteoclast detachment and exert osteoclast inhibition [48]. After interferon-gamma induction, nitrotyrosine production of human trabecular bone osteoblast increases, which means peroxynitrite is generated after inflammatory cytokines are stimulated in human osteoblast cells. The addition of peroxynitrite decreases the differentiation and proliferation of human trabecular bone osteoblasts [49]. All these findings suggest that high intracellular UA levels represent high inflammatory and oxidative stress, which contributes to the development of bone loss by disturbing osteoclast and osteoblast activities.