Inhibition of zoledronic acid derivatives with extended methylene linkers on osteoclastogenesis involve downregulation of JNK and Akt pathways

Abstract

Bisphosphonates (BPs), especially zoledronic acid (ZOL), are clinically used to treat osteolytic bone lesions. However, serious side‐effects may be also induced during the therapeutic process. To improve the BPs drugs, here, we investigated the effects of a series of ZOL derivatives with increasing number of methylene linker between the imidazole ring and the P–C–P backbone named IPrDP, IBDP, IPeDP, and IHDP on cell viability and receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast differentiation, function and apoptosis induction in mouse bone marrow‐derived macrophages (BMMs). Our results suggested that IPeDP and IHDP, which contains 4 and 5 methylene linkers, respectively, exerted lower toxicity on BMMs compared with ZOL, IPrDP, and IBDP, which contains 1, 2, and 3 methylene linkers respectively. At concentrations below cytotoxicity threshold, IPeDP and IHDP possessed strong abilities of antiosteoclast formation, antibone absorption, and inducing osteoclast apoptosis, which were similar to ZOL and more powerful than IPrDP and IBDP. The mechanism behind these effects of IPeDP and IHDP might involve the interference of small GTPases prenylation through suppression of mevalonate pathway. The downregulation of JNK and Akt phosphorylation and subsequent inhibition of the expression of c‐Fos and NFATc1 might also be involved. Our results supported the potential usage of IPeDP and IHDP to treat bone‐related disorders involving increased osteoclastogenesis. Our attempt to extend the methylene linker between the imidazole ring and the P–C–P backbone of ZOL also reveals some regularities between the structure and properties of the BPs drugs.

How zoledronic acid improves osteoporosis by acting on osteoclasts

“…Both the mitogen-activated protein kinases (MAPK) and NF-κB signaling pathways are closely related to osteoclast differentiation. The MAPK pathway, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, is critical for regulation of osteoclast differentiation ( Jin et al, 2018 ; Huang et al, 2019 ; Peng et al, 2021 ). ZA treatment can down-regulate JNK phosphorylation in a dose-dependent manner.…”

“…Therefore, how ZA regulates osteoclast differentiation through the RANKL pathway has always been a research hot spot. Through reviewing recent studies, it is not difficult to see that ZA exerts its regulatory effect on osteoclast differentiation through the entire RANKL signaling pathway, which can target many classical regulators or osteoclast differentiation-associated genes such as RANK, JNK, c-Jun, c-Fos and NFATc1 and DC-STAMP ( Huang et al, 2019 ; Mullin et al, 2019 ; Kodama and Kaito, 2020 ; Søe, 2020 ; Cheng et al, 2021 ; Peng et al, 2021 ; Huang et al, 2022 ). The non-canonical Wnt/Ca2+/CaMKII signaling pathway is another pathway by which ZA regulates osteoclast differentiation ( Wang et al, 2020 ).…”