. Author manuscript; available in PMC: 2014 Oct 1.

Published in final edited form as: Trends Biotechnol. 2013 Sep 6;31(10):10.1016/j.tibtech.2013.06.005. doi: 10.1016/j.tibtech.2013.06.005

Table.

Role of metal ions and their mechanism of action

	What role?	Mechanism of action
Li⁺	osteogenesis	➢ Inhibit glycogen synthase kinase3 (GSK3), which is a negative regulator of the Wnt signaling pathway [22,23]. ➢ Activates β-catenin mediated T cell factor (TCF) dependent transcription during bone and cartilage fracture healing [24]. β-catenin is known for its central role as signaling mediator in canonical Wnt signaling pathway
Zn²⁺	osteogenesis	➢ In the cellular microenvironment zinc is thought to stop the osteoclastic resorption process and stimulate the osteoblastic bone building process [33,34],
Mg²⁺	angiogenesis	➢ Magnesium induces nitric oxide production in endothelial cells which is essentially the same mechanism that VEGF uses to induce angiogenesis [37,38]
Sr²⁺	osteogenesis	➢ Strontium stimulates bone formation by a dual mode of action: stimulatory role on bone forming osteoblast cells, and inhibitory role on bone resorbing osteoclast cells. ➢ It activates calcium sensing receptor (CaSR) and downstream signalling pathways. This promotes osteoblast proliferation, differentiation and survival, while at the same time induces apoptosis in osteoclast cells resulting in decreased bone resorption [47]. ➢ Activation of the CaSR in osteoblasts [43,44] simultaneously increases osteoprotegerin (OPG) production and decreases receptor activator of nuclear factor kappa beta ligand (RANKL) expression [45]. ➢ OPG is a protein that inhibits RANKL induced osteoclastogenesis by operating as a decoy receptor for RANKL [46].
Cu⁺	angiogenesis	➢ Copper induced angiogenesis is probably caused by the upregulation of VEGF expression [55,57]. Copper induced toxicity: At high concentration, copper can generate reactive oxygen species (ROS) in presence of superoxide radical anions (*O₂⁻). These ROS induce oxidative damage to cells through DNA strand breaks and oxidation of bases [58,59].
Co²⁺	angiogenesis	➢ It is believed that Co²⁺ ions induce hypoxia on the cellular level by stabilizing the hypoxia-inducible factor (HIF)-1α [65,66]. ➢ Cell compensate to this hypoxic environment by expressing genes (such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO)) that promote neovascularization and angiogenesis. Cobalt induced toxicity: Like copper, cobalt also causes oxidative damage to cells by ROS [60]. Increased soluble Co²⁺ ions level might cause serious adverse reactions to the surrounding tissues as well as systemic toxicity. Co²⁺ ions can activate and increase bone resorbing osteoclast cells differentiation resulting in osteolysis aseptic implant loosening [61].
	Osteogenesis/angiogenesis	➢ Thought to play a role in the upregulation of transforming growth factor beta (TGF-β) and VEGF [67]
Mn^+2/+3	Osteogenesis	➢ Is thought to have implications in the parathyroid hormone (PTH) signaling pathway, a key regulator of calcium [87]. ➢ Manganese superoxide dismutase (MnSOD) is believed to neutralize the formation of reactive oxygen species, which contribute to increased osteoclastogenesis and decreased osteoblastogenesis [89]
Si⁺⁴	Osteogenesis/Angiogenesis	➢ Has been shown to induce angiogenesis by upregulating nitric oxide synthase (NOS) leading to increased VEGF production [83]. ➢ Osteogenic mechanisms are not well understood, but has been shown to play a vital role in the mineralization process [73]