Acute exposure to high dose γ-radiation results in transient activation of bone lining cells

Abstract

The present studies investigated the cellular mechanisms for the detrimental effects of high dose whole body γ-irradiation on bone. In addition, radioadaptation and bone marrow transplantation were assessed as interventions to mitigate the skeletal complications of irradiation. Increased trabecular thickness and separation and reduced fractional cancellous bone volume, connectivity density, and trabecular number were detected in proximal tibia and lumbar vertebra 14 days following γ-irradiation with 6 Gy. To establish the cellular mechanism for the architectural changes, vertebrae were analyzed by histomorphometry 1, 3, and 14 days following irradiation. Marrow cell density decreased within 1 day (67% reduction, p<0.0001), reached a minimum value after 3 days (86% reduction, p<0.0001), and partially rebounded by 14 days (30% reduction, p=0.0025) following irradiation. In contrast, osteoblast-lined bone perimeter was increased by 290% (1 day, p=0.04), 1230% (3 days, p<0.0001), and 530% (14 days, p=0.003), respectively. There was a strong association between radiation-induced marrow cell death and activation of bone lining cells to express the osteoblast phenotype (Pearson correlation −0.85, p<0.0001). An increase (p=0.004) in osteoclast-lined bone perimeter was also detected with irradiation. A priming dose of γ-radiation (0.5 mGy), previously shown to reduce mortality, had minimal effect on the cellular responses to radiation and did not prevent detrimental changes in bone architecture. Bone marrow transplantation normalized marrow cell density, bone turnover, and most indices of bone architecture following irradiation. In summary, radiation-induced death of marrow cells is associated with 1) a transient increase in bone formation due, at least in part, to activation of bone lining cells, and 2) an increase in bone resorption due to increased osteoclast perimeter. Bone marrow transplantation is effective in mitigating the detrimental effects of acute exposure to high dose whole body γ-radiation on bone turnover.

Quiescent Bone Lining Cells Are a Major Source of Osteoblasts During Adulthood

“…Both this study and other recent reports using a similar lineage tracing model confirm that BLCs arise from mature osteoblasts . Multiple factors including intermittent PTH, FGF2, sclerostin inhibition, mechanical loading, and irradiation have been shown to activate BLCs in vivo, however these studies did not show evidence of proliferation of BLCs following activation . In our study we demonstrate that following osteoblast ablation stimulus, BLCs are capable of proliferating and making a major contribution to new bone formation, while the contribution of iSMA and iGremlin mesenchymal progenitors is minimal.…”

“…One proposed function of BLCs is removal of demineralized matrix on the bone surface prior to bone formation . BLCs have been reported as a source of active osteoblasts after intermittent parathyroid hormone administration, basic fibroblast growth factor (FGF2) administration or following acute exposure to high dose γ‐radiation . This cell population therefore represents an alternative to MSCs as a source of osteoblasts in adult bone.…”

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease

“…Treatment with 1D11 did not however exacerbate tumor area in immunocompetent or immunocompromised mice. The absence of an effect on overall tumor burden is discordant with results observed for TGF-β inhibition by 1D11 in other tumor models, possibly because the medullary cavity is the primary site for MM unlike solid tumors such as breast and prostate that originate from other organ sites and are only metastatic to the bone marrow [15,31]. Primary bone marrow disease responds differently to TGF-β signaling than metastatic disease, and activation of signaling pathways may vary between progressive states [31].…”

“…Whole bone stiffness was defined as the slope of the initial linear portion of the curve, and strength was the peak force recorded. Using the moment of inertia (I min ) of the femoral mid-shaft and the distance between the centroid and bone surface in the anteroposterior direction (c min ) from µCT, we estimated the modulus and strength from flexural equations [31]. …”

Mechanical loading causes site-specific anabolic effects on bone following exposure to ionizing radiation

“…Total body gamma irradiation at high doses (5-6 Gy) significantly reduces the marrow cell density and stem cell population, which precedes deterioration of trabecular bone quality and quantity [35]. Irradiation of cultured osteoblasts and cell lines reduces collagen production, proliferation and differentiation and also increases sensitivity to apoptotic agents [36][37][38][39].…”