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. 2024 Jun;132(6):61301.
doi: 10.1289/EHP15263. Epub 2024 Jun 19.

Invited Perspective: New Insight into Cadmium-Related Osteoporosis Yields Hope for Prevention and Therapy

Lu Cai  1   2   3
Affiliations

Invited Perspective: New Insight into Cadmium-Related Osteoporosis Yields Hope for Prevention and Therapy

Lu Cai. Environ Health Perspect. 2024 Jun.
No abstract available

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Figures

Figure 1 is a schematic illustration depicting the potential mechanism where nuclear factor-erythroid 2-related factor 2 and nuclear factor-erythroid 2-related factor 1 synchronize together to prevent cadmium-mediated osteoporosis. Through a multifaceted mechanism, cadmium exposure promotes the synthesis of intracellular reactive oxygen species. Cadmium can adversely affect osteoblast differentiation directly via reactive oxygen species. Through the activation of long isoform nuclear factor-erythroid 2-related factor 1 by reactive oxygen species, the indirect stimulation stimulates osteoclast differentiation by up-regulating the expression of calcineurin-dependent 1, cytoplasmic, and nuclear factors in activated T cells. To negatively control the levels of reactive oxygen species, the master transcription factor nuclear factor-erythroid 2-related factor 2 regulates a number of antioxidant genes, such as catalase, superoxide dismutase, nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1, and metallothionein. The long isoform nuclear factor-erythroid 2-related factor 1, or nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 pathway leads to the ultimate prevention of osteoporosis. In the nuclear factor-erythroid 2-related factor, activators, such as sulforaphane, and metallothionein inducers, such as zinc, prevent cadmium-induced detrimental effects on osteoblasts and stimulation of osteoclasts.
Figure 1.
An illustration of the potential mechanism by which Nrf2 and Nrf1 coordinate to prevent cadmium (Cd)-mediated osteoporosis. Cd exposure may stimulate production of intracellular reactive oxygen species (ROS) via a complex mechanism. Through these ROSs, Cd directly damages osteoblast differentiation and indirectly induces osteoclast differentiation via ROS-mediated activation of L-Nrf1, which increases NFATc1 expression., The latter is a key driver controlling the genes that induce osteoclast differentiation and associated osteoporosis, as one of the direct downstream transcriptional targets of L-Nrf1. Nrf2, as a master transcription factor, regulates many antioxidant genes—including catalase (Cat), superoxide dismutase (SOD), NAD(P)H quinone dehydrogenase 1 (NQO-1), and metallothionein (MT)—to negatively control ROS levels.– Nrf2 activators, such as sulforaphane (SFN), and MT inducers, such as zinc, can synergistically or individually increase Nrf2 activation and MT expression.– Thus, both play important roles in preventing Cd-induced detrimental effects on osteoblasts and stimulation of osteoclasts via the L-Nrf1/NFATc1 pathway, leading to the final prevention of osteoporosis. The statements in this legend without citation are the author’s opinion based on the discussion in the main body of this perspective. Note: CtsK, cathespin K; HO-1, heme oxygenase; L-Nrf1, long isoform of nuclear factor erythroid 2-related factor 1; NAD(P)H, nicotinamide adenine dinucleotide phosphate; NFATc1, nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1; Nrf1, nuclear factor erythroid 2-related factor 1; Nrf2, nuclear factor erythroid 2-related factor 2.
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