Bortezomib Rescues Ovariectomy‐Induced Bone Loss via SMURF‐Mediated Ubiquitination Pathway

Abstract

A balance between bone formation by osteoblasts and bone resorption by osteoclasts is necessary to maintain bone health and homeostasis. As a cancer of plasma cells, multiple myeloma (MM) is accompanied with rapid bone loss and fragility fracture. Bortezomib has been used as a first-line for treating MM for decades. Recently, the potential protection of bortezomib on osteoporosis (OP) is reported; however, the specific mechanism involving bortezomib-mediated antiosteoporotic effect is undetermined. In the present study, we assessed the effects of in vitro bortezomib treatment on osteogenesis and osteoclastogenesis and the protective effect on bone loss in ovariectomized (OVX) mice. Our results indicated that bortezomib treatment increased osteogenic differentiation of MC3T3-E1 cells as evidenced by increased levels of matrix mineralization and osteoblast-specific markers. In bortezomib-treated bone marrow monocytes (BMMs), osteoclast differentiation was suppressed, substantiated by downregulated tartrate-resistant acid phosphatase- (TRAP-) positive multinucleated cells, areas of actin rings, pit formation, and osteoclast-specific genes. Mechanistically, bortezomib exerted a protective effect against OP through the Smad ubiquitination regulatory factor- (SMURF-) mediated ubiquitination pathway. Furthermore, in vivo intraperitoneal injection of bortezomib attenuated the bone microarchitecture in OVX mice. Accordingly, our findings corroborated that bortezomib might have future applications in the treatment of postmenopausal OP.

Aminooxyacetic acid hemihydrochloride inhibits osteoclast differentiation and bone resorption by attenuating oxidative phosphorylation

“…These high-energy-dependent osteoclast physiological activities are inhibited by AOAA. The OVX animal model is a classic model for simulating postmenopausal osteoclast over-formation and over-enhancement of function leading to osteoporosis (Lin et al, 2016;Fang et al, 2021). According to the results of our in vitro experiments, we further verified whether AOAA can affect osteoclasts in vivo.…”

Anti–NF-κB peptide derived from nuclear acidic protein attenuates ovariectomy-induced osteoporosis in mice

“…NF-κB inhibits osteoblast proliferation and differentiation ( 16 – 19 ) by inducing Smurf1 activation, leading to Smad ( 17 , 21 , 22 ), Runx2, and β-catenin degradation ( 20 – 23 ). In the present study, we found that 6A-8R decreases Smurf1 expression and increases Smad phosphorylation ( 52 ), promoting osteoblast differentiation (MC3T3-E1 cells).…”

“…IκBα induction was marginally inhibited by 6A-8R ( Figure 6D ). Furthermore, Smurf1 induction was inhibited by 6A-8R ( Figure 6E ); therefore, p-Smad1/5/9 was upregulated ( Figure 6E ) ( 52 ). There were no obvious changes in the expression of Runx2, β-catenin, or JunB as a result of the administration of 6A-8R ( Supplemental Figure 8 ).…”

The role of E3 ubiquitin ligases in bone homeostasis and related diseases

“…The concept of repurposing existing drugs for new uses has been granted by since 1997 143 . Although drugs targeted UPS have not been used for clinical therapy of osteoporosis, we list the drugs on the market or not to display the potential effect on bone loss ( Table 2 147 , 148 , 150 , 151 , 152 ). BTB is the first proteasomal inhibitor and confirmed to improve osteogenesis and restrain bone resorption during multiple myeloma (MM) to protect the skeletal system in mice and humans 144 , 145 .…”