Figure 3.

MOAs and AOPs underlying anemia‐independent detrimental effects on bone upon heavy metal exposure. Dysregulated osteogenesis and osteoclastogenesis are largely induced by alterations in the OPG/RANKL ratio and the altered expression of osteoblastic and osteoclastic genes. Oxidative stress and/or inflammation not only alter the expression of osteoblastic and osteoclastic genes, but also induce direct effects on bone. Additionally, oxidative stress and/or inflammation are actively involved in inhibiting the formation and enhancing the degradation of the extracellular bone matrix. Suppressed ALP activity and disturbed Ca and P homeostasis contribute to inhibited bone mineralization. MOAs, modes of action; AOPs, adverse outcome pathways; OPG, osteoprotegerin; RANKL, receptor activator of NF‐κB ligand; TRAP, tartrate‐resistant acid phosphatase; MMPs, matrix metalloproteinases; GAGs, glycosaminoglycans; PGs, proteoglycans; ALP, alkaline phosphatase.