Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, 89081 Ulm, Germany.
Institute for Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
Int J Mol Sci. 2023 May 23;24(11):9135. doi: 10.3390/ijms24119135.
Mast cells may contribute to osteoporosis development, because patients with age-related or post-menopausal osteoporosis exhibit more mast cells in the bone marrow, and mastocytosis patients frequently suffer from osteopenia. We previously showed that mast cells crucially regulated osteoclastogenesis and bone loss in ovariectomized, estrogen-depleted mice in a preclinical model for post-menopausal osteoporosis and found that granular mast cell mediators were responsible for these estrogen-dependent effects. However, the role of the key regulator of osteoclastogenesis, namely, receptor activator of NFκB ligand (RANKL), which is secreted by mast cells, in osteoporosis development has, to date, not been defined. Here, we investigated whether mast-cell-derived RANKL participates in ovariectomy (OVX)-induced bone loss by using female mice with a conditional deletion. We found that this deletion in mast cells did not influence physiological bone turnover and failed to protect against OVX-induced bone resorption in vivo, although we demonstrated that RANKL secretion was significantly reduced in estrogen-treated mast cell cultures. Furthermore, deletion in mast cells did not influence the immune phenotype in non-ovariectomized or ovariectomized mice. Therefore, other osteoclastogenic factors released by mast cells might be responsible for the onset of OVX-induced bone loss.
肥大细胞可能有助于骨质疏松症的发展，因为与年龄相关或绝经后骨质疏松症患者的骨髓中有更多的肥大细胞，肥大细胞增多症患者经常患有骨质疏松症。我们之前的研究表明，在绝经后骨质疏松症的临床前模型中，肥大细胞在卵巢切除、雌激素缺乏的小鼠中对破骨细胞生成和骨丢失具有重要的调节作用，并且发现颗粒肥大细胞介质是这些雌激素依赖性作用的原因。然而，到目前为止，尚未确定肥大细胞分泌的破骨细胞生成关键调节剂，即核因子-κB 配体（RANKL）在骨质疏松症发展中的作用。在这里，我们通过使用条件性缺失的雌性小鼠来研究肥大细胞衍生的 RANKL 是否参与卵巢切除（OVX）诱导的骨丢失。我们发现，这种肥大细胞中的缺失并不影响生理骨转换，并且不能在体内预防 OVX 诱导的骨吸收，尽管我们证明了雌激素处理的肥大细胞培养物中 RANKL 的分泌显着减少。此外，肥大细胞中的缺失并不影响非卵巢切除或卵巢切除小鼠的免疫表型。因此，肥大细胞释放的其他破骨细胞生成因子可能是导致 OVX 诱导的骨丢失的原因。
