Regulation of osteogenesis and osteoclastogenesis by zoledronic acid loaded on biodegradable magnesium-strontium alloy

Abstract

Inhibiting osteoclasts and osteoclast precursors to reduce bone resorption is an important strategy to treat osteoclast-related diseases, such as peri-prosthetic osteolysis. In this study, our objective was to study the role of zoledronic acid (ZA), as a highly potent and nitrogen-containing bisphosphonate, in promoting osteogenesis and inhibiting osteoclastogenesis properties of magnesium (Mg)-based implants. ZA was chemically associated with calcium phosphate (CaP) deposited on magnesium-strontium (Mg-Sr) alloy, which was confirmed by the morphological observation, phase composition and drug releasing via SEM, XRD spectrum and High Performance Liquid Chromatography (HPLC), respectively. The in vitro performances indicated that ZA-CaP bilayer coating Mg-Sr alloy could enhance the proliferation and the osteogenic differentiation as well as the mineralization of pre-osteoblasts, however, induce the apoptosis and inhibit the osteoclast differentiation. We further investigated the possible molecular mechanisms by using Quantitative real-time PCR (qRT-PCR) and Western Blotting, and the results showed that ZA-CaP bilayer coating Mg-Sr alloy could regulate the osteogenesis and osteoclastogenesis through the Estrogen Receptor α (ERα) and NF-κB signaling pathway. Moreover, ZA-CaP bilayer coating Mg-Sr alloy could regulate the cross talk of osteoblast-osteoclast and increase the ratio of OPG: RANKL in the co-culture system through OPG/RANKL/RANK signaling pathway, which promoting the balance of bone remodeling process. Therefore, these promising results suggest the potential clinical applications of ZA pretreated Mg-Sr alloys for bone defect repairs and periprosthetical osteolysis due to the excessive differentitation and maturation of osteoclasts.

Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

“…Other researchers also consider that bisphosphonates can enhance the replication of osteoblasts and sustain their survival. 24,45 High bone turnover level, which can be reflected by the high levels of CTX-1 and PINP according to the IFCC, 46 is a typical feature of postmenopausal women. 46 We show herein that OVX rats manifest similar increases in the serum levels of CTX-1 and PINP, indicating that the post OVX life in the rat nicely resembles the postmenopausal environment.…”

“…50–52 The counteraction of ZOL on OVX-caused bone mass loss may be mechanistically attributed, in part, to its inhibition of the OVX-caused activation of the RANKL-NF-κB signalling pathway that leads to enhanced differentiation of osteoclasts. 24,28,34 It cannot be excluded that the increase in the number of apoptotic osteoblasts in the OVX group and the decrease in the number of apoptotic osteoblasts in the ZOL group also involve the same molecular mechanism. However, this hypothetical thinking remains to be further determined, as osteoblasts are much smaller in size and it is difficult to quantify their IHC staining intensity.…”

“…21 ZOL has also been shown to effectively promote bone formation around implanted teeth, 22,23 inhibit bone resorption, and potentially promote bone formation mainly through its impact on osteoclasts and osteoblasts. 24 For these reasons, ZOL has gradually been introduced into stomatology as a highly effective bone resorption inhibitor. 22,23 Mechanistically, the two nitrogen atoms in the imidazole side chain of ZOL have a high affinity to hydroxyapatite in bone and can directly interfere with the adhesion of osteoclasts to the bone’s surface, causing ultrastructural changes of osteoclasts that eventually lead the cells to apoptosis.…”

High proportion strontium-doped micro-arc oxidation coatings enhance early osseointegration of titanium in osteoporosis by anti-oxidative stress pathway

“…Sr-doped implants are proved to significantly promote early osseointegration in both normal and osteoporotic conditions [ 21 , 22 ]. Previous studies on the mechanism of Sr 2+ promoting bone formation mainly focused on the inhibition of osteoclast maturation and the promotion of osteoblast differentiation [ 23 , 24 ]. However, the relevant molecular mechanisms have not been fully understood, particularly during osteoporosis.…”

Topical co‐administration of zoledronate with recombinant human bone morphogenetic protein-2 can induce and maintain bone formation in the bone marrow environment

“…Moreover, these biomaterials can offer novel therapeutic substitutes that can be used for the regeneration of bone cavities after the surgical removal of bone tumors, osteonecrosis lesions, or vertebral fractures. Local administrated of ZOL has been shown to directly suppress the bone resorption action of the osteoclasts in the local area [ 26 ]. The local effects of ZOL may also enable complications related to systemic bisphosphonate therapy, such as renal disorders or osteonecrosis of the jaw, to be avoided [ 27 ].…”