Molecular and cellular mechanisms for zoledronic acid-loaded magnesium-strontium alloys to inhibit giant cell tumors of bone

Abstract

In clinics, giant cell tumors of bone (GCTB) are removed by surgery. However, the resultant defects in bone still contain aggressive and metastatic GCTB cells that can recruit osteoclasts to damage bone, leading to new GCTB tumor growth and bone damage after tumor surgery. Hence, it is of high demand in developing a material that can not only fill the bone defects as an implant but also inhibit GCTB in the defect area as a therapeutic agent. More importantly, the molecular and cellular mechanism by which such a material inhibits GCTB growth has never been explored. To solve these two problems, we prepared a new biomaterial, the Mg-Sr alloys that were first coated with calcium phosphate and then loaded with a tumor-inhibiting molecule (Zoledronic acid, ZA). Then, by using a variety of molecular and cellular biological assays, we studied how the ZA-loaded alloys induced the death of GCTB cells (derived from patients) and inhibited their growth at the molecular and cellular level. At the cellular level, our results showed that ZA-loaded Mg-Sr alloys not only induced apoptosis and oxidative stress of GCTB cells, and suppressed their induced pre-osteoclast recruitment, but also inhibited their migration. At the molecular level, our data showed that ZA released from the ZA-loaded Mg-Sr alloys could significantly activate the mitochondrial pathway and inhibit the NF-κB pathway in the GCTB cells. Both mechanisms collectively induced GCTB cell death and inhibited GCTB cell growth. This work showed how a biomaterial inhibit tumor growth at the molecular and cellular level, increasing our understanding in the fundamental principle of materials-induced cancer therapy. This work will be interesting to readers in the fields of metallic materials, inorganic materials, biomaterials and cancer therapy.

Cytotoxicity of biodegradable magnesium alloy WE43 to tumor cells in vitro: Bioresorbable implants with antitumor activity?

“…Our study has established that the tumor cell death caused by the contact with the samples of the alloy was due to the induction of apoptosis. Similar conclusions were drawn in a study of the mechanism of cell death during incubation with other magnesium alloys . By employing phenotype Annexin V(+) PI(−) cells, we demonstrated that after 2–3 days of incubation with WE43, a significant part of the tumor cells, while still retaining signs of viability, was at an early stage of apoptosis.…”

Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review

“…ZA decreases the expression of RANK to inhibit the differentiation of osteoclasts through suppressing TNF-α and RANKL [ 39 – 41 ]. In addition, it is reported that ZA also inhibits NFATc1 and c-fos [ 17 , 26 , 42 ], suppresses NF-κB pathway through promoting the deubiquitination of TRAF6 [ 18 ], as well as the phosphorylation of tyrosine and the nuclear translocation of p65 [ 43 ].

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“…M-CSF promotes survival and proliferation of osteoclast precursors, and their differentiation into mature phagocytes, including osteoclasts [ 51 , 52 ]. ZA inhibits the activity, aggregation and migration of osteoclast precursor cells and macrophage [ 17 , 20 , 43 , 53 ] to prevent the differentiation of osteoclasts and induce apoptosis [ 54 ]. It is demonstrated that in the presence of M-CSF, ZA also inhibits RANKL-induced upregulation of RANK mRNA to suppress the differentiation of osteoclasts [ 41 ].…”

“…In addition, it is reported that ZA induces cancer cells apoptosis by inhibiting the production of RANKL in leukemia [ 82 ]. Moreover, ZA also increases the expression of pro-apoptotic protein Bax and decreases the expression of anti-apoptotic protein Bcl-2, increases the permeability of cell membrane, and induces caspase-3 dependent pathway, and finally induce apoptosis [ 43 ]. Furthermore, ZA also inhibits bone cancer metastasis through suppressing osteoclasts [ 21 , 22 , 41 , 58 , 83 – 85 ].…”

Bisphosphonate‐Functionalized Scaffolds for Enhanced Bone Regeneration

“…Bone defect healing is an intricate but methodical process that restores bone integrity and represents an intrinsic capacity of bone tissue . Most bone defects are repaired spontaneously, while the healing process can be complicated owing to insufficient regeneration when pathological states occur, such as severe trauma, osteoporosis, and bone tumors . Drug therapy is one of the main options for many diseases and is also suitable for the treatment of bone defects.…”