N = 6 in each group. *Indicates a significant difference (p < 0.05). It does this by increasing the activity and number of bone-building osteoblasts. It slows bone loss and helps to increase bone density in the spine. (2013) 28:973–9. Int J Mol Sci. 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 Chromium: (Moderate) Calcitonin is given to hypercalcemic patients to reduce serum calcium concentrations. Calcitonin treatment caused a further increase in Wnt10b in OVX rats. women [4]. The inhibition of osteoclastic resorption is the main mechanism by which calcitonin quickly decreases circulating calcium levels. Calcitonin functions to: stimulate osteoclast activity. The activity of peptides of the calcitonin family in bone. The serum levels of Wnt10b and bone formation and resorption markers were analyzed by ELISA. 298 0 obj <>stream Similar finding of change of Wnt10b concentration was noted in these groups. Liu H, Zhang N, Liu Y, Liu L, Yin G, En L. Effect of human Wnt10b transgene overexpression on peri-implant osteogenesis in ovariectomized rats. 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 This research was supported by research grants from the Ministry of Science and Technology (MOST 108-2320-B-016-013), Ministry of National Defense-Medical Affairs Bureau (MAB-108-0088), Tri-Service General Hospital (TSGH-D109137), and Chi Mei Medical Center (CMNDMC10713) to J-FS. This result implies that different kinds of anti-resorptive agents may induce distinct clastokines. Briefly, the chromogen was mixed with buffer immediately. ALP, alkaline phosphate; CKD, chronic kidney disease; CTX-1, type 1 carboxyterminal collagen fragments; Calca, calcitonin; Calcr, calcitonin receptor; CT, computer tomography; M-CSF, macrophage colony-stimulating factor; OVX, ovariectomy; P1NP, amino-terminal propeptide of type 1 procollagen; RANKL, receptor activator of nuclear factor kappa B ligand; S1P, sphingosine-1-phosphate; TGF-β1, transforming growth factor-beta 1; TRAP5b, tartrate-resistant acid phosphatase 5b. Though calcitonin is no longer considered an appropriate treatment option for osteoporosis, the effects of calcitonin on the coupling process between osteoclasts and osteoblasts remain uncertain. (2018) 40:134–41. Analysis of osteoblast mineralization was performed by ALP (A) and alizarin red staining (B). 11:613. doi: 10.3389/fendo.2020.00613. This is a limitation in our experiment. Calcitonin reduces calcium levels in the blood by two main mechanisms: It inhibits the activity of osteoclasts, which are the cells responsible for breaking down bone. This is an intricate and fantastic peptide. Harvested cells (contained monocytes) from bone marrow were extracted by centrifugation in an equal volume of Ficoll-Paque PLUS (17144002, GE Healthcare, Chicago, IL, USA). Growth Hormone doi: 10.1016/j.bone.2007.01.014, 15. Osteoblastic bone formation is communicated to osteoclastic bone resorption by positive and negative modulators (RANKL/OPG or WNT). Just so, does calcitonin increase osteoblast activity? The elemental mechanisms of calcitonin receptor (CTR) bone activity were discovered by Keller et al. doi: 10.1056/NEJM198708273170904, 4. Although calcitonin has significant calcium-lowing effects in some species, it appears to have a minimal influence on blood calcium … Osteoclasts dissolve bone tissue, which is replaced by new tissue formed … The scan was performed with 180° scanning at a voltage of 80 kVp and a current of 500 μA (7.9 W output). It might also help to reduce the risk of spine fractures and decrease the pain that results from those fractures. endstream endobj 254 0 obj <>stream J Endocrinol. Hurley DL, Tiegs RD, Wahner HW, Heath H III. Shyu JF, Shih C, Tseng CY, Lin CH, Sun DT, Liu T, et al. Figure 7. On the other hand, runx2 directly induces Wnt10b expression in osteoblasts (24). Many studies still have a great interest in calcitonin and the effect of the bone metabolism, physiological roles, and the activities. As shown in Figure 2A, a significant increase in Wnt10b was found in OVX rats compared with sham rats. The results obtained from a typical experiment were expressed as the means ± S.D. The concentrations in sera of Wnt10b and the bone resorption marker TRAP5b (tartrate-resistant acid phosphatase from 5b) were measured by ELISA (Wnt 10b (MBS2533600, MyBioSource, San Diego, CA, USA), TRAP5b (SB-TR102, Immunodiagnosticsystems, East Boldon, UK), and resorption marker CTX-1 (C-telopeptide of type I collagen) and formation markers osteocalcin and P1NP (type 1 procollagen amino-terminal—propeptide) were measured EIA (AC-06F1, AC-12F1, and AC-33F1 Immunodiagnosticsystems, UK). In osteoporosis the net rate of bone resorption exceeds the rate of bone formation, resulting in a decrease in bone mass. W:�\'�Ն]�ص�V6h�ko��O)����jtԥANԺ]���@Y�p�n+��旜P�;���nAcuS��2��]�5���{�,��1��ꚅ���`�>�O *Indicates a significant difference (p < 0.05). This molecule causes hypercalcemia by interacting with the PTH receptors, and thus increasing bone resorption, stimulating the renal reabsorption of Ca2+, and promoting the renal excretion of PO43-. Effect on the Bone Matrix Furthermore, the calcitonin indirectly increases the mineralization and the synthesis of the bone matrix, while the parathyroid hormone increases the formation of osteoclasts, increasing bone resorption. Calcitonin acts to decrease serum calcium concentrations in several ways. doi: 10.1016/S2213-8587(17)30188-2, 10. In bone, PTH enhances the release of calcium from the large reservoir contained in the bones. (2013) 19:179–92. 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. One function of this hormone is reducing osteoclast activity and bone … Salmon calcitonin inhibited osteoclastic bone resorption at concentrations of 1 pg/ml and above, while PTH and 1,25-dihydroxyvitamin D3 were without significant effect. Endocrinol., 08 September 2020 N Engl J Med. Remember, magnesium suppresses parathyroid osteoclast production, and stimulates calcitonin which reduces osteoclast activity -- so magnesium works to keep calcium in … Decreased Wnt10b and increased TRAP expressions were found in OVX rats as compared with sham rats. Osteoblasts were isolated from the calvariae of 1-day-old newborn SD rats and cultured in groups a-f medium as indicated in Materials and Methods. The volume of interest was 1.5–3.5 mm below the growth plate. PLoS ONE. Therefore, we hypothesize that calcitonin increases bone formation by inducing Wnt10b expression in osteoclasts. Figure 4. A total of 106 harvested cells were cultured in a 10 cm dish with osteoclast differentiation medium (α-MEM medium containing 10% fetal bovine serum (FBS, SH30088.03, GE Healthcare, USA), 50 ng/mL macrophage colony-stimulating factor (M-CSF, 400-28, PEPROTECH, Rocky Hill, NJ, USA), 50 ng/mL RANKL (315-11, PEPROTECH, USA), and 1% Antibiotic-Antimycotic Solution (30-004-CI, CORNING, Corning, NY, USA). Bone biopsies from patients treated with the drug show no effects on mineralization. Model of calcitonin-induced bone formation through action on osteoclasts. Decreased Wnt10b expression was found in OVX 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. Reconstructed cross-sections were reorientated, and the region of interest (ROI) was further selected. The present study provides further information about calcitonin at the molecular level of bone remodeling, and will thus help in future potential therapeutic studies on postmenopausal osteoporosis. Kuo YJ, Tsuang FY, Sun JS, Lin CH, Chen CH, Li Y, et al. c7H�����Β�q F���b�����j�H�uS,!���Y�͘m`����*�����4�F��4m^plzx���k���@��LJ�� � �]�]���p|�߁�/�����H/��kH�A�R.�A�J?Pʧ(ۂE7�4S��8�f�PΡdB�ȧ�V����}��E��� Xt��� ?��3���18�_u&�-g�>�ش��(�65`��,!JU��T��,���L�0���4��y�T�*�g��V�^��!�r^��RN������y�z�~0����%B��1�ipE� ޭ�6�>���^կ����~�+k\ ����������R�8��vq�����Y�W] After 8-week-old Sprague-Dawley (SD) rats were sacrificed, bone marrow from the tibiae and femurs were collected in 0.05% citric acid normal saline. To acquire appropriate data and verify our hypotheses, a number of valid techniques were employed in this study. Nat Commun. Collected sera were frozen at −80°C, and femurs were kept in alcohol at 4°C. doi: 10.1152/physrev.00066.2017, 7. Accordingly, Wnt proteins are likely to be involved in various aspects of bone biology, including osteoblastic and osteoclastic functions and endochondral bone formation. 250 0 obj <> endobj Calcitonin, a calcium regulatory hormone, strongly inhibits bone-resorbing activity of osteoclasts. Therefore, the role of osteoblast-derived Wnt10b could not be underestimated. doi: 10.1038/nm.3074, 13. Quantified ALP activity in osteoblasts was measured using an Alkaline Phosphatase Assay Kit (ab83369, Abcam, Cambridge, UK). This hormone is also referred to as thyrocalcitonin. Because the fluctuation in serum calcitonin levels does not have any obvious pathological outcomes, it has been suggested that calcitonin should have no physiological role in mammals. Meanwhile, calcitonin prevents excess amounts of calcium from deteriorating bones to enter the bloodstream. Association of anabolic effect of calcitriol with osteoclast-derived Wnt 10b secretion. After 4 weeks, OVX rats received a normal saline or calcitonin treatment for four additional weeks, after which the 6-month-old rats were sacrificed and underwent micro-CT analysis of the femoral bone (Figure 1). The authors acknowledge the technical support provided by the Instrument Center of the National Defense Medical Center; micro-CT scans, bone morphometric analysis, volumetric bone mineral density, and 3D image visualization were performed by Tzu-Hung Lin and Shen-Chuan Lo, Material and Chemical Research Laboratories, Industrial Technology Research Institute. T-HChu, J-FS, and P-JT: writing—original draft preparation. We hypothesize that calcitonin indirectly increases osteoblastic bone formation by inducing Wnt10b expression in osteoclasts. %PDF-1.6 %���� Uncoupling anti-resorptive (e.g., calcitonin, odanacatib, and saracatinib) would be better drugs because they could inhibit osteoclastic bone-resorbing activity while maintaining the bone formation attributed to sustained communication between osteoclasts and osteoblasts (9). Figures are representative reconstructed 3D images from each treatment group. The next day, after washing, the secondary Ab was applied at room temperature for 2 h. Finally, the membrane was treated with electrogenerated chemiluminescence reagent (RPN2235, GE Healthcare, USA) and detected using UVP ChemStudio PLUS (849-97-0851-03, Analytik Jena, Jena, Germany). Baron R, Gori F. Targeting WNT signaling in the treatment of osteoporosis. Calcitonin is a small peptide hormone secreted from the parafollicular cells of the thyroid gland in response to an increase in serum calcium. Calcitonin (from thyroid gland) decreases serum Ca2+ levels by causing the calcium to go back into the bones. Calcitonin increases femoral trabecular bone in ovariectomized osteoporotic rats. It is characterized by low bone mass resulting from the net increase of bone resorption over bone deposition and hence bones become brittle and fracture easily [4], [5]. No.3840, Thermo Scientific, Waltham, MA, USA) for 24 h, then transferred to 0.5 M EDTA, pH 8, for several days until a biopsy needle could be inserted in to the femur. ?�ѷ����J����w]��gI�Na�tR�a��R��S�y\$EM亱{��cY��9�ɦ�,'����(�fe� -�N8���n�gg���F5��*�1��s�8��:[����߫�"Y~_^GE2�&��l�}��� Scale bar = 20 μm. When given to patients with osteoporosis, calcitonin produces modest increases in bone mass because it slows the rate at which osteoclasts absorb bone. After deparaffinization, rehydration, and antigen retrieval and blocking, anti-Wnt10b Ab (NBP2-49165, Novus Biologicals, Centennial, CO, USA) was applied to the slides followed by incubation overnight. Western blot analysis revealed a significant time-dependent increase in Wnt10b expression in calcitonin-treated osteoclasts (Figure 5). Shi J, Chi S, Xue J, Yang J, Li F, Liu X. A decrease in serum calcium concentration and an increase in serum phosphorous concentration stimulate PTH secretion. These findings will help in future potential therapeutic studies of postmenopausal osteoporosis. Maruotti N, Corrado A, Neve A, Cantatore FP. (2002) 110:1849–57. 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. (1992) 134:141–7. doi: 10.1002/jcp.24326, 18. Finally, after the fourth time, centrifuged osteoblasts, and calvariae chips were cultured in α-MEM medium containing 10% FBS and 1% Antibiotic-Antimycotic Solution. Dev Cell. This suggests that the latter hormones do not increase bone resorption in intact bone through a direct effect on osteoclasts. The end result of calcitonin is DECREASE in serum calcium. Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation. As mentioned in chapter 11, the thyroid gland secretes a hormone called calcitonin . Although the 2D images also included cortical bone, the regions of interest containing trabecular bone in metaphysis were selected for subsequent quantification (Figure 1A). How does calcitonin work? (C) Quantitative results of the experiment shown in (A,B), and Wnt10b concentration in mediums of each group before cultured with osteoblasts. Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. Copp DH, Cheney B. Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood. (2012) 7:e40272. In osteoporosis the net rate of bone resorption exceeds the rate of bone formation, resulting in a decrease in bone mass. Interactions. J Cell Biochem. CT treatment increased Wnt10b expression. They were induced into osteoclasts by M-CSF and RANKL stimulation. Each series of experiments was repeated at least three times. We performed the analysis of the secondary trabecular bone area using 2 mm (236 slices) images. The micro architecture of the 18 femoral trabecular bones was investigated using micro-computed tomography (Skyscan 2211 Nanotomograph Micro-CT; Skyscan, Aartselaar, Belgium) at a resolution of 8.5 μm. 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. View all Received: 02 May 2020; Accepted: 27 July 2020; Published: 08 September 2020. Currently no pharmacological formulations are available to promote bone … However, the extent to which Wnt signaling is involved in bone physiology and disease is not yet fully understood. Calcitonin acts on calcitonin receptors in bone and possibly also the kidney and gastrointestinal tract, preventing the breakdown of bone and increasing its density. (2016) 2016:9392132. doi: 10.1155/2016/9392132, 17. doi: 10.1172/JCI200214218, 8. ��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 Pretreatment with C59, a Wnt secretion inhibitor, further enhanced the effect of calcitonin in increasing Wnt10b expression within the osteoclasts. C-YH, P-JT, T-HChe, and J-FS: writing—review and editing. The images were captured by microscopy (Axio Imager A2, Zeiss, Germany). It is well-documented that Wnt signaling plays a crucial role in many biological processes (e.g., cellular proliferation, tissue regeneration, and other systemic effects) (16). doi: 10.1016/j.coph.2018.04.011, 14. Bar = 500 μm. Nat. (2018) 10:1164. doi: 10.3390/nu10091164, 24. The prepared slides were then developed with the substrate chromogen of HRP-green (TA01HG-15, BioTnA, Kaohsiung, Taiwan). Scale bar = 50 μm. Uncoupling anti-resorptive, such as calcitonin, may modulate osteoblast mineralization through the controlled secretion of Wnt10b and S1P. 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>� Osteoclast-released Wnt-10b underlies cinacalcet related bone improvement in chronic kidney disease. stimulates bone production (anabolic) and prevents resorption inhibits activation of adenylyl cyclase transforming growth factor beta (TGF beta) (via increase in OPG) The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Physiol Rev. Bone formation analysis was performed in osteoblasts isolated from neonatal rat calvariae and cultured with the calcitonin-treated osteoclast-conditioned medium. Meanwhile, calcitonin prevents excess amounts of calcium from deteriorating bones to enter the bloodstream. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. The present study used micro-CT analysis to show that calcitonin alleviated bone loss in ovariectomy-induced osteoporotic rats (Figure 1). (A) Quantitative analysis of Wnt10b (B) Quantitative analysis of TRAP5b (C) Quantitative analysis of CTX-1 (D) Quantitative analysis of osteocalcin (E) Quantitative analysis of P1NP. doi: 10.1002/jcb.20284, 19. Bone marrow monocytes were isolated from femoral and tibial bones of 8-week-old SD rats. This helps minimize the risk that a person will experience hypercalcemia due to the calcium produced during the breakdown of bone in the body. 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). All authors have read and agreed to the published version of the manuscript. Front. Calcitonin works to control calcium and potassium levels. Because the calcitonin receptor is only expressed in osteoclasts, the effect of calcitonin on osteoblasts maybe indirect and mediated via osteoclasts. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. (2014) 5:5215. doi: 10.1038/ncomms6215, 9. Additionally, calcitonin function helps reduce the resorption of calcium in the kidneys. Calcitonin Salmon (synthetic origin) Nasal Spray should be used for women who cannot use other treatments or who choose not to use other treatments for osteoporosis. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. As a negative control, osteoblasts isolated from the calvariae of 1-day-old rats were cultured in a-MEM with or without C59 (a and b in Figure 6). Taken together, these results indicate that calcitonin induces bone formation by increasing the expression of Wnt10b in osteoclasts in ovariectomy-induced osteoporotic rats. Endocrinology. YC-1 alleviates bone loss in ovariectomized rats by inhibiting bone resorption and inducing extrinsic apoptosis in osteoclasts. Figure 5. doi: 10.1002/jbmr.1869, 6. For the alizarin red stain, each group was cultured for 18 days. Komori, T. Regulation of proliferation, differentiation and functions of osteoblasts by runx2. It has a short half-life. PTH is a bone anabolic agent and effective treatment for postmenopausal osteoporosis, maybe by its effect of increase Wnt10b production in osteoblasts (25). Inhibition of bone resorption, which would minimize fluxes of calcium from bone into blood. Baksh D, Boland GM, Tuan RS. Calcitonin increases Wnt10b and bone formation but decreases bone resorption in ovariectomized osteoporotic rats. In other words, calcitonin enhances excretion of calcium into urine. With regard to the indirect effect, two hypotheses have been postulated: (1) increase of 1,25-dihydroxyvitamin D3 plasma levels; (2) increased secretion of calcitonin, the hor- mone that inhibits osteoclastic bone resorption. Food and water were provided ad libitum. It does this by inhibiting the activity of the osteoclasts, the cells that break down bone. Figure 6. Sham-operated rats and ovariectomized (OVX) rats were treated as indicated in Figure 1. All groups were treated five times per week for 4 weeks. However, calcitonin is clinically used as a treatment option to treat osteoporosis. J Clin Invest. Calcitonin is known to stimulate renal 1,25 (OH)2 vitamin D (1,25D) production at a site in the proximal tubule different from parathyroid hormone and hypophosphatemia. osteoprotegerin (OPG) calcitonin .
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