National Defense Medical Center, Graduate Institute of Medical Sciences, Taipei, Taiwan.
Department of Surgery, Landseed International Hospital, Taoyuan, Taiwan.
Front Endocrinol (Lausanne). 2020 Sep 8;11:613. doi: 10.3389/fendo.2020.00613. eCollection 2020.
Calcitonin is a small peptide hormone secreted from the parafollicular cells of the thyroid gland in response to an increase in serum calcium. The inhibition of osteoclastic resorption is the main mechanism by which calcitonin quickly decreases circulating calcium levels. Although calcitonin pharmacologically acts on osteoclasts to prevent bone resorption, the results of studies on genetically modified animals have shown that the physiological effect of calcitonin is in the inhibition of osteoblastic bone formation. Because the calcitonin receptor is only expressed in osteoclasts, the effect of calcitonin on osteoblasts maybe indirect and mediated via osteoclasts. Wnt ligands are involved in various aspects of skeletal biology, including bone remodeling and endochondral bone formation. Wnt10b has recently been recognized as a clastokine, and is potentially a therapeutic target for treating bone disorders. However, the extent to which Wnt signaling is involved in bone physiology and disease is not yet fully understood. We hypothesize that calcitonin indirectly increases osteoblastic bone formation by inducing Wnt10b expression in osteoclasts. Micro-CT analysis revealed reduced bone loss in calcitonin-treated ovariectomized rats. The serum of animals treated with calcitonin had decreased TRAP5b and CTX-1 but increased osteocalcin, P1NP, and Wnt10b. Immunohistochemistry staining showed that the level of Wnt10b in the femur was increased in calcitonin-treated groups as compared with control groups. Hematopoietic mononuclear cells were separated from rat femur and tibia bone marrow, and were induced into osteoclasts following treatment with M-CSF and RANKL. In these cells, immunoconfocal microscopy and Western blot analysis showed that calcitonin induced an increase in Wnt10b expression. In a culture of osteoblasts isolated from neonatal rat calvariae, the calcitonin-treated osteoclast supernatant showed an increase in mineralization, as indicated by ALP and alizarin red staining. Taken together, these results indicate that calcitonin induces bone formation by increasing the expression of Wnt10b in osteoclasts in ovariectomy-induced osteoporotic rats. The present study provides in-depth information about the effects of calcitonin on bone remodeling and will thus help in the development of future potential therapeutic strategies for postmenopausal osteoporosis.
降钙素是一种由甲状腺滤泡旁细胞在血清钙增加时分泌的小肽激素。降钙素通过抑制破骨细胞吸收来快速降低循环钙水平。尽管降钙素在药理学上作用于破骨细胞以防止骨吸收，但对基因修饰动物的研究结果表明，降钙素的生理作用在于抑制成骨细胞的骨形成。由于降钙素受体仅在破骨细胞中表达，因此降钙素对成骨细胞的作用可能是间接的，并通过破骨细胞介导。Wnt 配体参与骨骼生物学的各个方面，包括骨重塑和软骨内骨形成。Wnt10b 最近被认为是一种破骨细胞因子，可能是治疗骨疾病的治疗靶点。然而，Wnt 信号在骨骼生理学和疾病中的作用程度尚未完全了解。我们假设降钙素通过诱导破骨细胞中 Wnt10b 的表达，间接增加成骨细胞的骨形成。Micro-CT 分析显示，降钙素治疗的去卵巢大鼠的骨丢失减少。用降钙素治疗的动物的血清中 TRAP5b 和 CTX-1 减少，但骨钙素、P1NP 和 Wnt10b 增加。免疫组织化学染色显示，与对照组相比，降钙素治疗组股骨中的 Wnt10b 水平增加。从大鼠股骨和胫骨骨髓中分离出造血单核细胞，并用 M-CSF 和 RANKL 诱导为破骨细胞。在这些细胞中，免疫共聚焦显微镜和 Western blot 分析显示，降钙素诱导 Wnt10b 表达增加。在从新生大鼠颅骨分离的成骨细胞的培养物中，降钙素处理的破骨细胞上清液显示矿化增加，如 ALP 和茜素红染色所示。综上所述，这些结果表明，降钙素通过增加去卵巢诱导的骨质疏松大鼠破骨细胞中 Wnt10b 的表达来诱导骨形成。本研究提供了关于降钙素对骨重塑影响的深入信息，因此有助于开发绝经后骨质疏松症的潜在治疗策略。
