Research

20 pages, 3933 KiB

Open AccessArticle

Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget’s Disease of Bone

by Emily M. Rabjohns, Rishi R. Rampersad, Arin Ghosh, Katlyn Hurst, Amanda M. Eudy, Jaime M. Brozowski, Hyun Ho Lee, Yinshi Ren, Anthony Mirando, Justin Gladman, Jessica L. Bowser, Kathryn Berg, Sachin Wani, Stuart H. Ralston, Matthew J. Hilton and Teresa K. Tarrant

Cells 2023, 12(7), 981; https://doi.org/10.3390/cells12070981 - 23 Mar 2023

Cited by 1 | Viewed by 1606

Abstract

Paget’s Disease of Bone (PDB) is a metabolic bone disease that is characterized by dysregulated osteoclast function leading to focal abnormalities of bone remodeling. It can lead to pain, fracture, and bone deformity. G protein-coupled receptor kinase 3 (GRK3) is an important negative [...] Read more.

Paget’s Disease of Bone (PDB) is a metabolic bone disease that is characterized by dysregulated osteoclast function leading to focal abnormalities of bone remodeling. It can lead to pain, fracture, and bone deformity. G protein-coupled receptor kinase 3 (GRK3) is an important negative regulator of G protein-coupled receptor (GPCR) signaling. GRK3 is known to regulate GPCR function in osteoblasts and preosteoblasts, but its regulatory function in osteoclasts is not well defined. Here, we report that Grk3 expression increases during osteoclast differentiation in both human and mouse primary cells and established cell lines. We also show that aged mice deficient in Grk3 develop bone lesions similar to those seen in human PDB and other Paget’s Disease mouse models. We show that a deficiency in Grk3 expression enhances osteoclastogenesis in vitro and proliferation of hematopoietic osteoclast precursors in vivo but does not affect the osteoclast-mediated bone resorption function or cellular senescence pathway. Notably, we also observe decreased Grk3 expression in peripheral blood mononuclear cells of patients with PDB compared with age- and gender-matched healthy controls. Our data suggest that GRK3 has relevance to the regulation of osteoclast differentiation and that it may have relevance to the pathogenesis of PDB and other metabolic bone diseases associated with osteoclast activation. Full article

(This article belongs to the Special Issue Advances in Bone Metabolism)

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12 pages, 6269 KiB

Open AccessArticle

7-Ketocholesterol Induces Oxiapoptophagy and Inhibits Osteogenic Differentiation in MC3T3-E1 Cells

by Jing Ouyang, Yaosheng Xiao, Qun Ren, Jishang Huang, Qingluo Zhou, Shanshan Zhang, Linfu Li, Weimei Shi, Zhixi Chen and Longhuo Wu

Cells 2022, 11(18), 2882; https://doi.org/10.3390/cells11182882 - 15 Sep 2022

Cited by 7 | Viewed by 1504

Abstract

7-Ketocholesterol (7KC) is one of the oxysterols produced by the auto-oxidation of cholesterol during the dysregulation of cholesterol metabolism which has been implicated in the pathological development of osteoporosis (OP). Oxiapoptophagy involving oxidative stress, autophagy, and apoptosis can be induced by 7KC. However, [...] Read more.

7-Ketocholesterol (7KC) is one of the oxysterols produced by the auto-oxidation of cholesterol during the dysregulation of cholesterol metabolism which has been implicated in the pathological development of osteoporosis (OP). Oxiapoptophagy involving oxidative stress, autophagy, and apoptosis can be induced by 7KC. However, whether 7KC produces negative effects on MC3T3-E1 cells by stimulating oxiapoptophagy is still unclear. In the current study, 7KC was found to significantly decrease the cell viability of MC3T3-E1 cells in a concentration-dependent manner. In addition, 7KC decreased ALP staining and mineralization and down-regulated the protein expression of OPN and RUNX2, inhibiting osteogenic differentiation. 7KC significantly stimulated oxidation and induced autophagy and apoptosis in the cultured MC3T3-E1 cells. Pretreatment with the anti-oxidant acetylcysteine (NAC) could effectively decrease NOX4 and MDA production, enhance SOD activity, ameliorate the expression of autophagy-related factors, decrease apoptotic protein expression, and increase ALP, OPN, and RUNX2 expression, compromising 7KC-induced oxiapoptophagy and osteogenic differentiation inhibition in MC3T3-E1 cells. In summary, 7KC may induce oxiapoptophagy and inhibit osteogenic differentiation in the pathological development of OP. Full article

(This article belongs to the Special Issue Advances in Bone Metabolism)

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21 pages, 4355 KiB

Open AccessArticle

Notch2 Blockade Mitigates Methotrexate Chemotherapy-Induced Bone Loss and Marrow Adiposity

by Yaser Peymanfar, Yu-Wen Su and Cory J. Xian

Cells 2022, 11(9), 1521; https://doi.org/10.3390/cells11091521 - 02 May 2022

Cited by 6 | Viewed by 2501

Abstract

Childhood cancer methotrexate (MTX) chemotherapy often causes bone growth impairments, bone loss, and increased risks of fractures during or after treatment, for which the pathobiology is unclear and there is a lack of specific treatment. Our time course analyses of long bones from [...] Read more.

Childhood cancer methotrexate (MTX) chemotherapy often causes bone growth impairments, bone loss, and increased risks of fractures during or after treatment, for which the pathobiology is unclear and there is a lack of specific treatment. Our time course analyses of long bones from rats receiving intensive MTX treatment (mimicking a clinical protocol) found decreased trabecular bone volume, increased osteoclast formation and activity, increased adipogenesis in the expense of osteogenesis from the bone marrow stromal cells at days 6 and 9 following the first of five daily MTX doses. For exploring potential mechanisms, PCR array expression of 91 key factors regulating bone homeostasis was screened with the bone samples, which revealed MTX treatment-induced upregulation of Notch receptor NOTCH2, activation of which is known to be critical in skeletal development and bone homeostasis. Consistently, increased Notch2 activation in bones of MTX-treated rats was confirmed, accompanied by increased expression of Notch2 intracellular domain protein and Notch target genes HEY1, HES1 and HEYL. To confirm the roles of Notch2 signalling, a neutralising anti-Notch2 antibody or a control IgG was administered to rats during MTX treatment. Microcomputed tomography analyses demonstrated that trabecular bone volume was preserved by MTX+anti-Notch2 antibody treatment. Anti-Notch2 antibody treatment ameliorated MTX treatment-induced increases in osteoclast density and NFATc1 and RANKL expression, and attenuated MTX-induced bone marrow adiposity via regulating Wnt/β-catenin signalling and PPARγ expression. Thus, Notch2 signalling plays an important role in mediating MTX treatment-induced bone loss and bone marrow adiposity, and targeting Notch2 could be a potential therapeutic option. Full article

(This article belongs to the Special Issue Advances in Bone Metabolism)

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14 pages, 2119 KiB

Open AccessEditor’s ChoiceArticle

PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling

by Doron Cohn-Schwartz, Yeshai Schary, Eran Yalon, Zoe Krut, Xiaoyu Da, Edward M. Schwarz, Dan Gazit, Gadi Pelled and Zulma Gazit

Cells 2022, 11(5), 897; https://doi.org/10.3390/cells11050897 - 05 Mar 2022

Cited by 4 | Viewed by 1965

Abstract

The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic [...] Read more.

The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic effect of PTH are both dependent on endothelial PTH receptor-1 (PTHR1) signaling. To evaluate our hypothesis, we used multiple transgenic mouse lines, and their wild-type counterparts as a control. In addition to endothelial-specific PTHR1 knock-out mice, we used mice in which PTHR1 was engineered to be constitutively active in collagen-1α+ osteoblasts, to assess the effect of PTH signaling activation exclusively in osteoprogenitors. To characterize resident cell recruitment and osteogenic activity, mice in which the Luciferase reporter gene is expressed under the Osteocalcin promoter (Oc-Luc) were used. Mice were implanted with calvarial allografts and treated with either PTH or PBS. A micro-computed tomography-based structural analysis indicated that the induction of bone formation by PTH, as observed in wild-type animals, was not maintained when PTHR1 was removed from endothelial cells. Furthermore, the induction of PTH signaling exclusively in osteoblasts resulted in significantly less bone formation compared to systemic PTH treatment, and significantly less osteogenic activity was measured by bioluminescence imaging of the Oc-Luc mice. Deletion of the endothelial PTHR1 significantly decreased the PTH-induced formation of narrow blood vessels, formerly demonstrated in wild-type mice. However, the exclusive activation of PTH signaling in osteoblasts was sufficient to re-establish the observed PTH effect. Collectively, our results show that endothelial PTHR1 signaling plays a key role in PTH-induced osteogenesis and has implications in angiogenesis. Full article

(This article belongs to the Special Issue Advances in Bone Metabolism)

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15 pages, 6612 KiB

Open AccessArticle

Geniposide Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts by Mediating the GLP-1R/ABCA1 Axis

by Yizhou Zheng, Yaosheng Xiao, Di Zhang, Shanshan Zhang, Jing Ouyang, Linfu Li, Weimei Shi, Rui Zhang, Hai Liu, Qi Jin, Zhixi Chen, Daohua Xu and Longhuo Wu

Cells 2021, 10(12), 3424; https://doi.org/10.3390/cells10123424 - 06 Dec 2021

Cited by 17 | Viewed by 2418 | Correction

Abstract

Background: Overexposure to glucocorticoid (GC) produces various clinical complications, including osteoporosis (OP), dyslipidemia, and hypercholesterolemia. Geniposide (GEN) is a natural iridoid compound isolated from Eucommia ulmoides. Our previous study found that GEN could alleviate dexamethasone (DEX)-induced differentiation inhibition of MC3T3-E1 cells. However, whether [...] Read more.

Background: Overexposure to glucocorticoid (GC) produces various clinical complications, including osteoporosis (OP), dyslipidemia, and hypercholesterolemia. Geniposide (GEN) is a natural iridoid compound isolated from Eucommia ulmoides. Our previous study found that GEN could alleviate dexamethasone (DEX)-induced differentiation inhibition of MC3T3-E1 cells. However, whether GEN protected against Dex-induced cholesterol accumulation in osteoblasts was still unclear. Methods: DEX was used to induce rat OP. Micro-CT data was obtained. The ALP activity and mineralization were determined by the staining assays, and the total intracellular cholesterol was determined by the ELISA kits. The protein expression was detected by western blot. Results: GEN ameliorated Dex-induced micro-structure damages and cell differentiation inhibition in the bone trabecula in rats. In MC3T3-E1 cells, Dex enhanced the total intracellular cholesterol, which reduced the activity of cell proliferation and differentiation. Effectively, GEN decreased DEX-induced cholesterol accumulation, enhanced cell differentiation, and upregulated the expression of the GLP-1R/ABCA1 axis. In addition, inhibition of ABAC1 expression reversed the actions of GEN. Treatment with Exendin9-39, a GLP-1R inhibitor, could abrogate the protective activity of GEN. Conclusions: GEN ameliorated Dex-induced accumulation of cholesterol and inhibition of cell differentiation by mediating the GLP-1R/ABCA1 axis in MC3T3-E1 cells. Full article

(This article belongs to the Special Issue Advances in Bone Metabolism)

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Review

Jump to: Research, Other

23 pages, 1931 KiB

Open AccessReview

HIF-1α Regulates Bone Homeostasis and Angiogenesis, Participating in the Occurrence of Bone Metabolic Diseases

by Wei Chen, Panfeng Wu, Fang Yu, Gaojie Luo, Liming Qing and Juyu Tang

Cells 2022, 11(22), 3552; https://doi.org/10.3390/cells11223552 - 10 Nov 2022

Cited by 17 | Viewed by 3623

Abstract

In the physiological condition, the skeletal system’s bone resorption and formation are in dynamic balance, called bone homeostasis. However, bone homeostasis is destroyed under pathological conditions, leading to the occurrence of bone metabolism diseases. The expression of hypoxia-inducible factor-1α (HIF-1α) is regulated by [...] Read more.

In the physiological condition, the skeletal system’s bone resorption and formation are in dynamic balance, called bone homeostasis. However, bone homeostasis is destroyed under pathological conditions, leading to the occurrence of bone metabolism diseases. The expression of hypoxia-inducible factor-1α (HIF-1α) is regulated by oxygen concentration. It affects energy metabolism, which plays a vital role in preventing bone metabolic diseases. This review focuses on the HIF-1α pathway and describes in detail the possible mechanism of its involvement in the regulation of bone homeostasis and angiogenesis, as well as the current experimental studies on the use of HIF-1α in the prevention of bone metabolic diseases. HIF-1α/RANKL/Notch1 pathway bidirectionally regulates the differentiation of macrophages into osteoclasts under different conditions. In addition, HIF-1α is also regulated by many factors, including hypoxia, cofactor activity, non-coding RNA, trace elements, etc. As a pivotal pathway for coupling angiogenesis and osteogenesis, HIF-1α has been widely studied in bone metabolic diseases such as bone defect, osteoporosis, osteonecrosis of the femoral head, fracture, and nonunion. The wide application of biomaterials in bone metabolism also provides a reasonable basis for the experimental study of HIF-1α in preventing bone metabolic diseases. Full article

(This article belongs to the Special Issue Advances in Bone Metabolism)

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19 pages, 1623 KiB

Open AccessFeature PaperReview

Current Status and Prospects of Targeted Therapy for Osteosarcoma

by Zunguo Hu, Shuang Wen, Zijun Huo, Qing Wang, Jiantao Zhao, Zihao Wang, Yanchun Chen, Lingyun Zhang, Fenghua Zhou, Zhangyu Guo, Huancai Liu and Shuanhu Zhou

Cells 2022, 11(21), 3507; https://doi.org/10.3390/cells11213507 - 05 Nov 2022

Cited by 19 | Viewed by 2603

Abstract

Osteosarcoma (OS) is a highly malignant tumor occurring in bone tissue with a high propensity to metastasize, and its underlying mechanisms remain largely elusive. The OS prognosis is poor, and improving the survival of OS patients remains a challenge. Current treatment methods such [...] Read more.

Osteosarcoma (OS) is a highly malignant tumor occurring in bone tissue with a high propensity to metastasize, and its underlying mechanisms remain largely elusive. The OS prognosis is poor, and improving the survival of OS patients remains a challenge. Current treatment methods such as surgical approaches, chemotherapeutic drugs, and immunotherapeutic drugs remain ineffective. As research progresses, targeted therapy is gradually becoming irreplaceable. In this review, several treatment modalities for osteosarcoma, such as surgery, chemotherapy, and immunotherapy, are briefly described, followed by a discussion of targeted therapy, the important targets, and new technologies for osteosarcoma treatment. Full article

(This article belongs to the Special Issue Advances in Bone Metabolism)

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Other

Jump to: Research, Review

5 pages, 783 KiB

Open AccessComment

Oxiapoptophagy in Age-Related Diseases. Comment on Ouyang et al. 7-Ketocholesterol Induces Oxiapoptophagy and Inhibits Osteogenic Differentiation in MC3T3-E1 Cells. Cells 2022, 11, 2882

by Imen Ghzaiel, Thomas Nury, Amira Zarrouk, Anne Vejux and Gérard Lizard

Cells 2022, 11(22), 3612; https://doi.org/10.3390/cells11223612 - 15 Nov 2022

Cited by 2 | Viewed by 1024

Abstract

Due to the increase in life span and life expectancy, which can, however, be more or less pronounced depending on the economic, social and cultural context [...] Full article

(This article belongs to the Special Issue Advances in Bone Metabolism)

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