Cargando…

Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeu...

Descripción completa

Detalles Bibliográficos
Autores principales: Hung, Kuo-Chin, Chang, Jia-Feng, Hsu, Yung-Ho, Hsieh, Chih-Yu, Wu, Mai-Szu, Wu, Mei-Yi, Chiu, I-Jen, Syu, Ren-Si, Wang, Ting-Ming, Wu, Chang-Chin, Hung, Lie-Yee, Zheng, Cai-Mei, Lu, Kuo-Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698938/
https://www.ncbi.nlm.nih.gov/pubmed/33218086
http://dx.doi.org/10.3390/ijms21228712
_version_ 1783615940667113472
author Hung, Kuo-Chin
Chang, Jia-Feng
Hsu, Yung-Ho
Hsieh, Chih-Yu
Wu, Mai-Szu
Wu, Mei-Yi
Chiu, I-Jen
Syu, Ren-Si
Wang, Ting-Ming
Wu, Chang-Chin
Hung, Lie-Yee
Zheng, Cai-Mei
Lu, Kuo-Cheng
author_facet Hung, Kuo-Chin
Chang, Jia-Feng
Hsu, Yung-Ho
Hsieh, Chih-Yu
Wu, Mai-Szu
Wu, Mei-Yi
Chiu, I-Jen
Syu, Ren-Si
Wang, Ting-Ming
Wu, Chang-Chin
Hung, Lie-Yee
Zheng, Cai-Mei
Lu, Kuo-Cheng
author_sort Hung, Kuo-Chin
collection PubMed
description We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast–osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast–osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = −0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/β-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid–bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast–osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.
format Online
Article
Text
id pubmed-7698938
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-76989382020-11-29 Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease Hung, Kuo-Chin Chang, Jia-Feng Hsu, Yung-Ho Hsieh, Chih-Yu Wu, Mai-Szu Wu, Mei-Yi Chiu, I-Jen Syu, Ren-Si Wang, Ting-Ming Wu, Chang-Chin Hung, Lie-Yee Zheng, Cai-Mei Lu, Kuo-Cheng Int J Mol Sci Article We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast–osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast–osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = −0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/β-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid–bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast–osteoclast homeostasis in Cinacalcet therapy for CKD-MBD. MDPI 2020-11-18 /pmc/articles/PMC7698938/ /pubmed/33218086 http://dx.doi.org/10.3390/ijms21228712 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hung, Kuo-Chin
Chang, Jia-Feng
Hsu, Yung-Ho
Hsieh, Chih-Yu
Wu, Mai-Szu
Wu, Mei-Yi
Chiu, I-Jen
Syu, Ren-Si
Wang, Ting-Ming
Wu, Chang-Chin
Hung, Lie-Yee
Zheng, Cai-Mei
Lu, Kuo-Cheng
Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease
title Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease
title_full Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease
title_fullStr Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease
title_full_unstemmed Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease
title_short Therapeutic Effect of Calcimimetics on Osteoclast–Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease
title_sort therapeutic effect of calcimimetics on osteoclast–osteoblast crosslink in chronic kidney disease and mineral bone disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698938/
https://www.ncbi.nlm.nih.gov/pubmed/33218086
http://dx.doi.org/10.3390/ijms21228712
work_keys_str_mv AT hungkuochin therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT changjiafeng therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT hsuyungho therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT hsiehchihyu therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT wumaiszu therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT wumeiyi therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT chiuijen therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT syurensi therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT wangtingming therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT wuchangchin therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT hunglieyee therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT zhengcaimei therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease
AT lukuocheng therapeuticeffectofcalcimimeticsonosteoclastosteoblastcrosslinkinchronickidneydiseaseandmineralbonedisease