Thus, it is fundamentally important to uncover the mechanism by which calcitonin affects osteoblastic bone formation through its actions on osteoclasts (Figure 7). Immunohistochemistry staining showed that the level of Wnt10b in the femur was increased in calcitonin-treated groups as compared with control groups. doi: 10.1016/j.devcel.2005.03.016, 20. Bone biopsies from patients treated with the drug show no effects on mineralization. This result implies that different kinds of anti-resorptive agents may induce distinct clastokines. Int J Mol Sci. h��XmO�8�+�:q�klK+���-Ҳ���q:ć��J���&���f;om�V���t��g��ZfԊpʡ� @kM��Pb5֖X# 7�0�@�0���� j$�@�\,A�QDP��b"P7�ɠ�1D�8��D:K�dZF���r��A� �Bw+�R4[��^1 doi: 10.1056/NEJM198708273170904, 4. In contrast to the escape from calcitonin-induced inhibition seen in parathyroid hormone (PTH)-stimulated bones, the inhibitory effect of calcitonin in TGF-beta 1-stimulated bones persisted in long-term cultures (144 h). J Clin Endocrinol Metab. Osteoclasts also communicate to osteoblasts by clastokines (Wnt10b and S1P). Because the calcitonin receptor is only expressed in osteoclasts, the effect of calcitonin on osteoblasts maybe indirect and mediated via osteoclasts. (1984) 102:281–6. J Clin Invest. Day TF, Guo X, Garrett-Beal L, Yang, Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Briefly, the chromogen was mixed with buffer immediately. Bone formation analysis was performed in osteoblasts isolated from neonatal rat calvariae and cultured with the calcitonin-treated osteoclast-conditioned medium. (C) Quantitative results of the experiment shown in (A,B), and Wnt10b concentration in mediums of each group before cultured with osteoblasts. As a result, it can increase bone mass dramatically. Low Levels Low levels of calcitonin lead to osteopenia, while low levels of parathyroid hormone lead to hypothyroidism. Curr Opin Pharmacol. doi: 10.1677/joe.0.1020281, 3. This theory is, however, not widely accepted, and the existing consensus is that calcitonin plays a significant role in protecting the skeleton under circumstances of calcium stress (5, 6). Figure 4. However, C59 is a Wnt inhibitor, not specific for Wnt10b. OVX or a sham operation was performed in 4-month-old female Sprague–Dawley rats. Wnt ligands have been widely studied by means of various osteoblastic models and, later, animal models. The calcitonin-induced increase of ALP and alizarin red staining was reduced by C59 cotreatment (f in Figure 6). h�b```e``Z������A��X�r,��1�����f���W�C�� �V�) ���Dk� [r3z��� �6���߭�3��Nde�;��;��O�{(f���2�������������V8�X��� ^� �;:�Z��: Further investigations in this research area are necessary to comprehend the scope of Wnt effects on bone metabolism and the effectiveness of Wnt-based therapeutics on bone structure and functions. doi: 10.1210/jc.2011-2332, 11. Calcitonin works to control calcium and potassium levels. ��0+��˸�|W��S��^6�l��\�����~ 6Ós�0>`�b�2D,d60 1�'l� z��v���� �4b�c�@F����� �l�ᢉ�%o �� '�_� 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. Shyu JF, Shih C, Tseng CY, Lin CH, Sun DT, Liu T, et al. The high bone mass attributed to increased bone formation has been found in both Calca KO and Calcr KO mice (7, 8), even though Calcr did not manifest in osteoblasts. The serum levels of Wnt10b and bone formation and resorption markers were analyzed by ELISA. Collected sera were frozen at −80°C, and femurs were kept in alcohol at 4°C. An increase in serum calcium concentrations helps to reduce bone resorption and loss of bone mass, and offsets the effect of calcitonin in lowering serum calcium levels. 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. In animals, calcitonin binds to osteoclasts, preventing bone resorption. J Cell Biochem. Calcitonin is a human hormone that is also found in salmon, however, man-made calcitonin is made using DNA recombinant technology and does not use salmon. Calcitonin treatment caused a further increase in Wnt10b in OVX rats. Finally, after the fourth time, centrifuged osteoblasts, and calvariae chips were cultured in α-MEM medium containing 10% FBS and 1% Antibiotic-Antimycotic Solution. In short, calcitonin probably has indirect effects on osteoblasts that are mediated via osteoclasts. This is because the Wnt family is characterized by at least 19 different glycoproteins, each of which is responsible for triggering multiple signaling cascades. Physiol Rev. Boland GM, Perkins G, Hall DJ, Tuan RS. However, the extent to which Wnt signaling is involved in bone physiology and disease is not yet fully understood. In many ways, calcitonin counteracts parathyroid hormone (PTH) and vitamin D. This suggests that the latter hormones do not increase bone resorption in intact bone through a direct effect on osteoclasts. When the osteoclasts break down bone tissue, the calcium enters the bloodstream. Copyright © 2020 Hsiao, Chen, Chu, Ting, Tsai and Shyu. No use, distribution or reproduction is permitted which does not comply with these terms. The inhibition of osteoclastic resorption is the main mechanism by which calcitonin quickly decreases circulating calcium levels. doi: 10.1371/journal.pone.0040272, 12. It does this by increasing the activity and number of bone-building osteoblasts. (1962) 193:381–2. Each blot is representative of at least three replicate experiments. In ovariectomized rats, the effects of calcitonin on the protection of bone loss and Wnt10b expression were determined by micro-CT, bone histomorphometry, and immunohistochemistry analysis. However, the role of Wnt ligands in skeletal physiology and disease is not fully comprehended. The activity of peptides of the calcitonin family in bone. Anti-resorptive inhibit osteoclast resorption, which usually causes the inhibition of bone formation. Taken together, these results demonstrate that calcitonin induces bone formation by increasing the expression of Wnt10b in osteoclasts in ovariectomy-induced osteoporotic rats (Figure 7). Copp DH, Cheney B. Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood. Moreover, osteoblastic mineralization was enhanced in conditioned medium derived from calcitonin-treated osteoclasts (Figure 6). Consequently, further studies are needed to dissect the underlying mechanisms and corresponding physiological relevance during bone remodeling. Calcitonin suppresses the activity of cells in the bone called osteoclasts. N = 6 in each group. Calcitonin is secreted in response to an increase in calcium. doi: 10.1038/nm.3074, 13. The elemental mechanisms of calcitonin receptor (CTR) bone activity were discovered by Keller et al. After blocking, the membrane was incubated with primary Ab overnight at 4°C. Calcitonin Calcitonin is a hormone naturally produced in the thyroid. Recent studies of the regulatory mechanisms for the cross-talk between osteoclasts and osteoblasts have identified several bone formation-stimulating osteoclast-derived factors (i.e., clastokines) and matrix-derived growth factors, and the authors have asserted that these factors may contribute to the future design of novel osteoanabolic compounds (10). Medicines that interact with calcitonin may either decrease its effect, affect how long it … In addition, osteoblasts may also secrete Wnt10b which is interesting issue worth of more study. Immunohistochemistry labeling of Wnt10b (green) and TRAP stain (red) were performed near resorption zone of growth plate in femoral bone. Then, anti-Wnt10b Ab was applied over night at 4°C. PTH is a bone anabolic agent and effective treatment for postmenopausal osteoporosis, maybe by its effect of increase Wnt10b production in osteoblasts (25). Quantitation of these results (Figure 1B) indicated that OVX led to significant bone loss, increased trabecular separation, and decreased trabecular number compared with the control sham operation. We performed the analysis of the secondary trabecular bone area using 2 mm (236 slices) images. In the CT treatment group, increase of Wnt10b and decrease of TRAP expressions were also found near resorption zone of growth plate in femoral bone. interacts directly with the osteoclast via cell-surface receptors; estrogen (via decrease in RANKL) stimulates bone production (anabolic) and prevents resorption… N = 6 in each group. When given to patients with osteoporosis, calcitonin produces modest increases in bone mass because it slows the rate at which osteoclasts absorb bone. (2013) 228:1428–32. In osteoclasts obtained from M-CSF- and RANKL-treated hematopoietic mononuclear cells isolated from rat femur and tibia bone marrow, the expression of Wnt10b was determined by ELISA, Western blot, and confocal microscopy analysis. Each series of experiments was repeated at least three times. Reconstructed cross-sections were reorientated, and the region of interest (ROI) was further selected. Using in vivo OVX rats and in vitro osteoclast and osteoblast cultures, we show that calcitonin induces bone formation by increasing the expression of Wnt10b in osteoclasts in ovariectomy-induced osteoporotic rats. ��ژ�RU�=���v�VÝS���vΕk�P�%܇�.��F������N������~�� �wG>���}��7��pW����B?��x�Fi��G>�� �����Z�_����%u�;v0~h�`Z��c���j>-ݧ�G'�{[ A��@�?��-9̯�bҎ)��Wo��zw�ﵧy:o��*ސ ㄓ����>K��HtP�>Ea����-����.�7n(m�Ђ5ޣ�����=�i�.5�43M�mȋc���u All rats were acclimatized under accepted laboratory conditions (temperature was 22 ± 2°C, and humidity was 50 ± 10%). (2014) 5:5215. doi: 10.1038/ncomms6215, 9. Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts. The results obtained from a typical experiment were expressed as the means ± S.D. Osteoclast-released Wnt-10b underlies cinacalcet related bone improvement in chronic kidney disease. Med. Ring artifacts and beam-hardening corrections were also performed using this software. Briefly, the study asserted that losing CTR in osteoclasts would increase the levels of sphingolipid transporter 2 (spinster 2, SPNS2), an exporter protein required for the secretion of sphingosine-1-phosphate (S1P), which can effectively induce bone formation. J]&O��&���j��E�;�O$ܼp$4p�=������v,�ɖ�e�U���:/��:L���P���%�"L�j��?RgHeM�l�o�BPH� ���j��4J �5���t���X�,gDsN�X��hpO@����q�[B��4� �}����f��h䗶����mj��ڵ5�z�u�7>� This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Wang JW, Yeh CB, Chou SJ, Lu KC, Chu TH, Chen Y, et al. Received: 02 May 2020; Accepted: 27 July 2020; Published: 08 September 2020. Femurs were taken from experimental rats, then washed several times in PBS and fixed overnight in formalin substitute solution (FX1075, Cancer Diagnostics, Durham, NC, USA). Baron R, Hesse E. Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives. Calcitonin: A hormone produced by the thyroid gland that lowers the levels of calcium and phosphate in the blood and promotes the formation of bone. It is evident that the pharmacological function of calcitonin is to inhibit bone resorption through lowered levels of circulating calcium; nevertheless, the physiological role of calcitonin remains unclear. PLoS ONE. T-HChe, C-YH, J-FS, Y-NT, and T-HChu: methodology and investigation. Int J Mol Sci. Calcitonin receptors are coupled to both cAMP-PKA- and Ca (2+)-PKC (protein kinase C)-mediated … TGF-beta 1-induced stimulation of 45Ca release was inhibited by calcitonin, acetazolamide, and the biphosphonate AHPrBP, three different osteoclast inhibitors. Many studies still have a great interest in calcitonin and the effect of the bone metabolism, physiological roles, and the activities. Osteoclast Inhibition decreases bone resorption; Molecules that inhibit bone resorption . Calcitonin is secreted in direct response to serum hypercalcemia and may prevent large oscillations in serum calcium levels and excessive loss of body calcium. On the other hand, runx2 directly induces Wnt10b expression in osteoblasts (24). As mentioned in chapter 11, the thyroid gland secretes a hormone called calcitonin . Zheng CM, Hsu YH, Wu CC, Lu CL, Liu WC, Zheng Q, et al. Just so, does calcitonin increase osteoblast activity? 298 0 obj <>stream doi: 10.1002/jcb.20284, 19. All groups were treated five times per week for 4 weeks. women [4]. Osteoporosis, characterized by remarkable losses of bone mineral density and strength, results in fragility fractures and subsequent high morbidity and mortality (9). In osteoporosis the net rate of bone resorption exceeds the rate of bone formation, resulting in a decrease in bone mass. The femurs were decalcified in Decalcifying Solution (REF. Calcitonin treatment increases the osteoclastic Wnt10b expression in metaphysis of femoral bone in ovariectomy-induced osteoporotic rats. Nature. As shown in Figure 2A, a significant increase in Wnt10b was found in OVX rats compared with sham rats. During the observation period a significant increase in bone resorption and a significant drop in intestinal calcium absorption was observed. *Indicates a significant difference (p < 0.05). Currently, existing murine models suggest that Wnt3a, Wnt5a, and Wnt10b are critical for osteoblast regulation, whereas Wnt14 is important for endochondral bone formation (18–20). J-FS and T-HChe: resources. N = 6 in each group. The distribution and intensity of Wnt10b was analyzed using a confocal microscope (LSM 510, Zeiss, Oberkochen, Germany). Therefore, we hypothesize that calcitonin increases bone formation by inducing Wnt10b expression in osteoclasts. 271 0 obj <>/Filter/FlateDecode/ID[]/Index[250 49]/Info 249 0 R/Length 100/Prev 489290/Root 251 0 R/Size 299/Type/XRef/W[1 3 1]>>stream

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