Passin Vanessa, Ledesma-Colunga Maria G, Altamura Sandro, Muckenthaler Martina U, Baschant Ulrike, Hofbauer Lorenz C, Rauner Martina
Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.
IUBMB Life. 2025 Jan;77(1):e2928. doi: 10.1002/iub.2928. Epub 2024 Nov 18.
Iron is an essential element for physiological cellular processes, but is toxic in excess. Iron overload diseases are commonly associated with low bone mass. Increased bone resorption by osteoclasts as well as decreased bone formation by osteoblasts have been implicated in bone loss under iron overload conditions. However, the exact contribution of individual cell types has not yet been formally tested. In this study, we aimed to investigate the role of osteoclast precursors in iron overload-induced bone loss. To that end, we used clodronate liposomes to deplete phagocytic cells (including macrophages and osteoclast precursors) in male C57BL/6J mice that were exposed to ferric derisomaltose. Bone microarchitecture and bone turnover were assessed after 4 weeks. The application of clodronate resulted in the efficient depletion of circulating myeloid-lineage cells by about 70%. Depletion of osteoclast precursors mitigated iron overload-induced trabecular bone loss at the lumbar vertebrae and distal femur. While clodronate treatment led to a profound inhibition of bone turnover in control mice, it significantly reduced osteoclast numbers in iron-treated mice without further impacting the bone formation rate or serum PINP levels. Our observations suggest that even though bone formation is markedly suppressed by iron overload, osteoclasts also play a key role in iron overload-induced bone loss and highlight them as potential therapeutic targets.
铁是生理细胞过程中的必需元素，但过量时具有毒性。铁过载疾病通常与低骨量相关。破骨细胞引起的骨吸收增加以及成骨细胞引起的骨形成减少与铁过载条件下的骨质流失有关。然而，尚未正式测试个体细胞类型的确切作用。在本研究中，我们旨在研究破骨细胞前体在铁过载诱导的骨质流失中的作用。为此，我们使用氯膦酸脂质体来消耗暴露于麦芽糖铁的雄性C57BL/6J小鼠中的吞噬细胞（包括巨噬细胞和破骨细胞前体）。4周后评估骨微结构和骨转换。氯膦酸的应用导致循环髓系细胞有效消耗约70%。破骨细胞前体的消耗减轻了铁过载诱导的腰椎和股骨远端小梁骨丢失。虽然氯膦酸治疗导致对照小鼠的骨转换受到显著抑制，但它显著降低了铁处理小鼠中的破骨细胞数量，而没有进一步影响骨形成率或血清PINP水平。我们的观察结果表明，尽管铁过载会明显抑制骨形成，但破骨细胞在铁过载诱导的骨质流失中也起着关键作用，并突出了它们作为潜在治疗靶点的地位。
