Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis

Abstract

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis.-Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.

Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss

“…We were able to confirm our previous reports and saw a significant bone loss 4 weeks post‐FRT (Fig. A , B ) . To confirm the presence of senescent cells 28 days post‐FRT, we stained for SA‐β‐gal activity in both NR and R femurs, and found a significant 4.4‐fold increase in the SA‐β‐gal + cells on the bone surface in the R femurs (Fig.…”

“…Four‐month‐old Col2‐Cre‐Td+Tomato male mice received radiation (24 Gy) in a 5‐mm region of the right femoral metaphysis, accompanied with intermittent treatments on day 0 and 14, with either vehicle ( n = 4 mice) or D+Q ( n = 4 mice); bones were collected on day 42 post‐FRT and processed for frozen sectioning. The TUNEL assay was carried out according to the manufacturer's instructions (ApopTag Fluorescein In Situ Detection Kit; EMD Millipore, Billerica, MA, USA) and as described …”

Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do?

“…These agents include recombinant parathyroid hormone (PTH 1–34‐Teriparatide), growth hormone, insulin‐like growth factor‐I, prostaglandin agonists, statins (lovastatin), decoy receptor neutralizing Activin A (Sotatercept), neutralizing anti‐DKK1 antibody (BHQ880), and neutralizing anti‐sclerostin antibodies (Romosozumab and Blosozumab) (Khan et al, ; Weinerman & Usera, ). Dual‐functional agents stimulate bone formation and decrease bone resorption and include Strontium Ranelate and Bortezomib (Proteasome and NF‐kB signaling pathway inhibitor) (Chandra et al, ). BPs, due to their prolonged response, high efficiency and lower costs, are to date considered the first line of management for controlling different types of OD (Weinerman & Usera, ).…”

Periosteal Mesenchymal Progenitor Dysfunction and Extraskeletally-Derived Fibrosis Contribute to Atrophic Fracture Nonunion

“…This clinical relationship between radiation therapy, fracture, and healing provided the impetus for utilizing radiation as a model to induce and study atrophy during bone regeneration. Previously, we used a focal irradiator (Small Animal Radiation Research Platform [SARRP]), which can mimic clinical focal radiation therapy in rodents with submillimeter accuracy, to delineate the mechanism of radiation damage on metaphyseal trabecular bone and to investigate potential treatments for this devastating condition . Here, we extended our research to traumatic bone fracture and established a highly reproducible and clinically relevant mouse nonunion model.…”

“…Previously, we used a focal irradiator (Small Animal Radiation Research Platform [SARRP]), which can mimic clinical focal radiation therapy in rodents with submillimeter accuracy, to delineate the mechanism of radiation damage on metaphyseal trabecular bone and to investigate potential treatments for this devastating condition. (10)(11)(12) Here, we extended our research to traumatic bone fracture and established a highly reproducible and clinically relevant mouse nonunion model. Characterization of this model revealed the underlying cellular and molecular mechanisms of nonunion formation.…”