Department of Biological and Biomedical Engineering, McGill University, Montreal, QC, Canada.
Shriners Hospital for Children-Canada, Montreal, QC, Canada.
J Bone Miner Res. 2021 Apr;36(4):803-813. doi: 10.1002/jbmr.4245. Epub 2021 Feb 8.
Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of myelofibrosis is linked to aberrant megakaryocyte development and function. Null and loss-of-function mutations in MPIG6B, which codes for the inhibitory heparan sulfate receptor G6b-B, result in severe macrothrombocytopenia, large megakaryocyte clusters, and focal primary myelofibrosis in mice and humans. We investigated the development of osteosclerosis in Mpig6b null (Mpig6b ) mice. Although male and female Mpig6b mice presented with elevated bone marrow megakaryocyte number and macrothrombocytopenia, female Mpig6b mice developed progressive splenomegaly starting at 8 weeks of age. Micro-computed tomography (μCT) of femurs showed that female Mpig6b mice had increased cortical thickness and reduced bone marrow area starting at 8 weeks of age and developed occlusion of the medullary cavity by trabeculae by 16 weeks of age. In contrast, male Mpig6b mice developed only a small number of trabeculae in the medullary cavity at the proximal diaphysis and demonstrated a temporary decrease in bone volume fraction and trabecular thickness at 16 weeks. Ovariectomy of 10-week-old female Mpig6b mice prevented the development of medullary cavity osteosclerosis, whereas orchiectomy of male Mpig6b mice did not exacerbate their disease. Importantly, ovariectomized female Mpig6b mice also demonstrated improvement in spleen weight compared to sham-operated Mpig6b mice, establishing estrogen as a contributing factor to the severity of the megakaryocyte-driven osteosclerosis. © 2021 American Society for Bone and Mineral Research (ASBMR).
患有慢性骨髓纤维化的患者常患有骨硬化症，这与骨痛有关，并可能导致骨髓衰竭。骨髓纤维化的发病机制与巨核细胞发育和功能异常有关。编码抑制性硫酸乙酰肝素受体 G6b-B 的 MPIG6B 的无效和缺失突变导致严重的巨血小板减少症、大巨核细胞簇和在小鼠和人类中出现局灶性原发性骨髓纤维化。我们研究了 Mpig6b 缺失（Mpig6b）小鼠中骨硬化症的发展。尽管雄性和雌性 Mpig6b 小鼠的骨髓巨核细胞数量增加且出现巨血小板减少症，但雌性 Mpig6b 小鼠从 8 周龄开始出现进行性脾肿大。股骨的微计算机断层扫描（μCT）显示，雌性 Mpig6b 小鼠从 8 周龄开始出现皮质厚度增加和骨髓面积减少，并在 16 周龄时出现骨髓腔小梁闭塞。相比之下，雄性 Mpig6b 小鼠仅在近骨干的骨髓腔内形成少量小梁，并且在 16 周时表现出骨体积分数和小梁厚度的暂时减少。对 10 周龄雌性 Mpig6b 小鼠进行卵巢切除术可防止骨髓腔骨硬化症的发展，而对雄性 Mpig6b 小鼠进行睾丸切除术不会加重其疾病。重要的是，卵巢切除术的雌性 Mpig6b 小鼠的脾脏重量也比假手术的 Mpig6b 小鼠有所改善，这表明雌激素是巨核细胞驱动的骨硬化症严重程度的一个促成因素。
