Irradiation‐induced osteocyte damage promotes HMGB1‐mediated osteoclastogenesis in vitro

Abstract

Irradiation‐induced bone loss is widely reported, especially in radiotherapy‐induced osteoporosis. In addition to the mechanism of osteogenesis inhibition and osteoclastogenesis promotion, the regulation effect of osteocytes, which also send signals to modulate osteoclastogenesis, should be elucidated. In this study, the effect of irradiation on osteocyte and its accommodation to osteoclastogenesis via the release of high mobility group box 1 (HMGB1) was explored. Furthermore, the control response of HMGB1 inhibitor on receptor activator of nuclear factor‐κB ligand (RANKL) and osteoprotegerin (OPG) expression in osteocyte and osteocyte‐induced osteoclastogenesis was assessed. It was observed that irradiated osteocyte‐like MLO‐Y4 cells exhibited polygonal‐shaped morphological changes and shortened dendrites, inhibited cell viability and induced cellular apoptosis, along with the reduction in dendritic E11 protein/messenger RNA expression at a doses of 4 Gy. Additionally, the secretion of HMGB1 in supernatants was promoted, accompanied by the decreased OPG and elevated RANKL expression. When the RAW264.7 cells were cocultured with irradiated MLO‐Y4 cells or its conditioned medium, enhanced migration and differentiation of osteoclast precursor was observed, and this difference was alleviated with anti‐HMGB1 neutralizing antibody. In conclusion, this study demonstrated that irradiation deteriorated osteocytes’ potential to promote recruitment and differentiation of osteoclast precursor via stimulating HMGB1 release and subsequent elevation of RANKL/OPG level. This study will assist in designing the intervention programs for irradiation‐induced bone loss.

Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases

“…Trigger the generation of pro-inflammatory and pro-osteoclastic factors via positive feedback loop [109][110][111][112]114 FADD Trigger a caspase cascade; induce GCs-induced apoptosis 6,118 Sclerostin Promote osteocyte cells death upon unloading; inhibit bone formation 53,107,108 BNIP3 Promote cell death during hypoxia 60,62 CCN2 Promote osteocyte apoptosis upon excess mechanical stress 33,69 TNF-α Stimulate osteocyte apoptosis upon inflammation and cancer 92,115,116 Caspase-3 Regulate osteocyte apoptosis via physical interactions in mechanistic stimulus 27,127 CTSK Breakdown the bone matrix adjacent to the osteocyte; increase the size of the osteocyte lacunae and mineralization decrease vitality of osteocytes 23 DMP-1 Regulate osteocyte formation and phosphate homeostasis; involve in osteocytic apoptosis 29,84,154 Pyk2 Promote GCs-induced osteocytic apoptosis via focal adhesion 82 Panx-1 Promote fatigue-induced osteocytic apoptosis 160 Anti-apoptotic function SOD2 Suppress aging and loss of bone mass; decrease degeneration of the osteocyte LCN 24,61 AMPK Protects against Hcy-induced osteocyte apoptosis 96,101,102 NO Maintain osteocytic vitality by pulsatile fluid flow 44,54,100…”

The Influence of Radiation on Bone and Bone Cells—Differential Effects on Osteoclasts and Osteoblasts

“…Furthermore, IR reduces cellular viability in osteocytes and increases the apoptosis rate in these cells. Interestingly, irradiated osteocytes can promote osteoclastogenesis through the release of HMGB1 (high mobility group box 1) followed by an elevation of the RANK-L/OPG (osteoprotegerin) levels, indicating a key role for osteocytes in IR-induced bone loss during cancer therapy [ 104 ]. Moreover, in vivo studies have proven that very high doses of X-rays (30 Gy) lead to significant changes in the osteocyte lacunae network, with a decrease in osteocytes in woven bone, accompanied by increased numbers of empty lacunae [ 105 ].…”

Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity

“…The cause for an early and transient increase in osteoclast activity is unclear, and perhaps due to signals between other cells, including osteocytes. Bone is made up of approximately 90-95% osteocytes [56]. These cells serve as the conductors of homeostasis.…”

“…While osteocytes are buried in the matrix of lacunae, their dendritic processes allow sensory information from bone stressors (including radiation) to trigger the release of inhibitory or stimulatory signals, which drive the response of osteoclasts, osteoblasts, and osteoprogenitor cells. A link exists between osteocyte dendritic morphology and apoptosis from radiation and subsequent differentiation of osteoclasts [37,56,57], perhaps through expression of receptor activator of nuclear factor kappa B-ligand RANKL, lowered osteoprotegerin (OPG), and high-mobility group box 1 protein (HMGB-1) identified from the irradiated osteocyte cell line MLO-Y4.…”

“…signals between other cells, including osteocytes. Bone is made up of approximately 90%-95% osteocytes [56]. These cells serve as the conductors of homeostasis.…”