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Cellular and Molecular Regulation of Bone Remodeling

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Tissues and Organs".

Deadline for manuscript submissions: closed (10 May 2022) | Viewed by 18834

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Special Issue Editor

Dr. Zhenqiang Yao

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Guest Editor

School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Ave, Box 626, Rochester, NY 14642, USA
Interests: osteoclasts and osteoblasts related to osteoporosis; rheumatoid arthritis; bone metastatic cancer

Special Issue Information

Dear Colleagues,

Imbalance of bone remodeling caused by the enhanced osteoclastic bone resorption and /or reduced osteoblastic bone formation is the basis of trabecular and cortical bone loss in a variety of bone diseases, including but not limited to osteoporosis, rheumatoid arthritis, bone metastatic cancers, aseptic loosening of arthroplasty and periodontal disease. The fate of osteoclasts is determined by the interactions of their monocyte/macrophage progenitor cells with the supporting cells, including osteoblast, mesenchymal progenitor cell (MPC), osteocyte, T cell and B cell through producing cytokines M-CSF, RANKL, OPG and TNFα. Osteoblast differentiation is determined by the fate of MPCs, which also differentiate into adipocytes and fibroblasts, regulated by various hormones, cytokines, chemokines, growth factors, etc. Currently, osteoporosis is still un-curable, although anti-resorptive and anabolic drugs are available. The special issue of “Cellular and molecular regulation of bone remodeling” welcome original research or review articles on the basic, translational and clinical studies that address the cellular and molecular regulations of osteoclast and osteoblast as well as their reciprocal interactions with the supporting cells in both normal or pathological conditions.

Dr. Zhenqiang Yao
Guest Editor

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Keywords

osteoclast
osteoblast
osteocyte
chondrocyte
osteoporosis
osteoarthritis
rheumatoid arthritis
bone metastatic cancers

Published Papers (5 papers)

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Research

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9 pages, 1491 KiB

Open AccessCommunication

Mice with Targeted Knockout of Tetraspanin 3 Exhibit Reduced Trabecular Bone Mass Caused by Decreased Osteoblast Functions

by Weirong Xing, Sheila Pourteymoor, Chandrasekhar Kesavan, Gustavo A. Gomez and Subburaman Mohan

Cells 2022, 11(6), 977; https://doi.org/10.3390/cells11060977 - 12 Mar 2022

Cited by 1 | Viewed by 1843

Abstract

Tetraspanin3 (TSPAN3) was identified as a binding partner of claudin11 (CLDN11) in osteoblasts and other cell types. Mice with targeted disruption of Cldn11 exhibited trabecular bone mass deficit caused by reduced bone formation and osteoblast function. To determine if the disruption of CLDN11 interacting protein gene Tspan3 results in a similar skeletal phenotype as that of Cldn11 knockout (KO) mice, we generated homozygous Tspan3 KO and heterozygous control mice and characterized their skeletal phenotypes at 13 weeks of age. Micro-CT measurements of the secondary spongiosa of the distal femur revealed 17% and 29% reduction in trabecular bone volume adjusted for tissue volume (BV/TV) in the male and female mice, respectively. Similarly, trabecular BV/TV of the proximal tibia was reduced by 19% and 20% in the male and female mice, respectively. The reduced trabecular bone mass was caused primarily by reduced trabecular thickness and number, and increased trabecular spacing. Consistent with the reduced bone formation as confirmed by histomorphometry analyses, serum alkaline phosphatase was reduced by 11% in the KO mice as compared with controls. Our findings indicate that TSPAN3 is an important positive regulator of osteoblast function and trabecular bone mass, and the interaction of TSPAN3 with CLDN11 could contribute in part to the bone forming effects of Cldn11 in mice. Full article

(This article belongs to the Special Issue Cellular and Molecular Regulation of Bone Remodeling)

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20 pages, 2663 KiB

Open AccessArticle

The Osteocyte Stimulated by Wnt Agonist SKL2001 Is a Safe Osteogenic Niche Improving Bioactivities in a Polycaprolactone and Cell Integrated 3D Module

by Yangxi Liu, Xiaojie Ruan, Jun Li, Bo Wang, Jie Chen, Xiaofang Wang, Pengtao Wang and Xiaolin Tu

Cells 2022, 11(5), 831; https://doi.org/10.3390/cells11050831 - 28 Feb 2022

Cited by 9 | Viewed by 2648

Abstract

Finding and constructing an osteogenic microenvironment similar to natural bone tissue has always been a frontier topic in orthopedics. We found that osteocytes are targeting cells controlling bone anabolism produced by PTH (JBMR 2017, PMID: 27704638), and osteocytes with activated Wnt signaling orchestrate bone formation and resorption (PNAS 2015, PMID: 25605937). However, methods for taking advantage of the leading role of osteocytes in bone regeneration remain unexplored. Herein, we found that the osteocytes with SKL2001-activated Wnt signaling could be an osteogenic microenvironment (SOOME) which upregulates the expression of bone transcription factor Runx2 and Bglap and promotes the differentiation of bone marrow stromal cell ST2 into osteoblasts. Interestingly, 60 μM SKL2001 treatment of osteocytic MLO-Y4 for 24 h maintained Wnt signaling activation for three days after removal, which was sufficient to induce osteoblast differentiation. Triptonide, a Wnt inhibitor, could eliminate this differentiation. Moreover, on day 5, the Wnt signaling naturally decreased to the level of the control group, indicating that this method of Wnt-signaling induction is safe to use. We quickly verified in vivo function of SOOME to a good proximation in 3D bioprinted modules composed of reciprocally printed polycaprolactone bundles (for support) and cell bundles (for bioactivity). In the cell bundles, SOOME stably supported the growth and development of ST2 cells, the 7-day survival rate was as high as 91.6%, and proliferation ability increased linearly. Similarly, SOOME greatly promoted ST2 differentiation and mineralization for 28 days. In addition, SOOME upregulated the expression of angiopoietin 1, promoted endothelial cell migration and angiogenesis, and increased node number and total length of tubes and branches. Finally, we found that the function of SOOME could be realized through the paracrine pathway. This study reveals that osteocytes with Wnt signaling activated by SKL2001 are a safe osteogenic microenvironment. Both SOOME itself and its cell-free culture supernatant can improve bioactivity for osteoblast differentiation, with composite scaffolds especially bearing application value. Full article

(This article belongs to the Special Issue Cellular and Molecular Regulation of Bone Remodeling)

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15 pages, 6670 KiB

Open AccessArticle

The Cytoplasmic Dynein Associated Protein NDE1 Regulates Osteoclastogenesis by Modulating M-CSF and RANKL Signaling Pathways

by Bhaba K. Das, Jyoti Gogoi, Aarthi Kannan, Ling Gao, Weirong Xing, Subburaman Mohan and Haibo Zhao

Cells 2022, 11(1), 13; https://doi.org/10.3390/cells11010013 - 22 Dec 2021

Cited by 6 | Viewed by 3337

Abstract

Cytoskeleton organization and lysosome secretion play an essential role in osteoclastogenesis and bone resorption. The cytoplasmic dynein is a molecular motor complex that regulates microtubule dynamics and transportation of cargos/organelles, including lysosomes along the microtubules. LIS1, NDE1, and NDEL1 belong to an evolutionary conserved pathway that regulates dynein functions. Disruption of the cytoplasmic dynein complex and deletion of LIS1 in osteoclast precursors arrest osteoclastogenesis. Nonetheless, the role of NDE1 and NDEL1 in osteoclast biology remains elusive. In this study, we found that knocking-down Nde1 expression by lentiviral transduction of specific shRNAs markedly inhibited osteoclastogenesis in vitro by attenuating the proliferation, survival, and differentiation of osteoclast precursor cells via suppression of signaling pathways downstream of M-CSF and RANKL as well as osteoclast differentiation transcription factor NFATc1. To dissect how NDEL1 regulates osteoclasts and bone homeostasis, we generated Ndel1 conditional knockout mice in myeloid osteoclast precursors (Ndel1^ΔlysM) by crossing Ndel1-floxed mice with LysM-Cre mice on C57BL/6J background. The Ndel1^ΔlysM mice developed normally. The µCT analysis of distal femurs and in vitro osteoclast differentiation and functional assays in cultures unveiled the similar bone mass in both trabecular and cortical bone compartments as well as intact osteoclastogenesis, cytoskeleton organization, and bone resorption in Ndel1^ΔlysM mice and cultures. Therefore, our results reveal a novel role of NDE1 in regulation of osteoclastogenesis and demonstrate that NDEL1 is dispensable for osteoclast differentiation and function. Full article

(This article belongs to the Special Issue Cellular and Molecular Regulation of Bone Remodeling)

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12 pages, 2473 KiB

Open AccessArticle

Prolyl Hydroxylase Domain-Containing Protein 3 Gene Expression in Chondrocytes Is Not Essential for Bone Development in Mice

by Weirong Xing, Sheila Pourteymoor, Gustavo A. Gomez, Yian Chen and Subburaman Mohan

Cells 2021, 10(9), 2200; https://doi.org/10.3390/cells10092200 - 26 Aug 2021

Cited by 4 | Viewed by 1834

Abstract

We previously showed that conditional disruption of the Phd2 gene in chondrocytes led to a massive increase in long bone trabecular bone mass. Loss of Phd2 gene expression or inhibition of PHD2 activity by a specific inhibitor resulted in a several-fold compensatory increase in Phd3 expression in chondrocytes. To determine if expression of PHD3 plays a role in endochondral bone formation, we conditionally disrupted the Phd3 gene in chondrocytes by crossing Phd3 floxed (Phd3^flox/flox) mice with Col2α1-Cre mice. Loss of Phd3 expression in the chondrocytes of Cre⁺; Phd3^flox/flox conditional knockout (cKO) mice was confirmed by real time PCR. At 16 weeks of age, neither body weight nor body length was significantly different in the Phd3 cKO mice compared to Cre⁻; Phd3^flox/flox wild-type (WT) mice. Areal BMD measurements of total body as well as femur, tibia, and lumbar skeletal sites were not significantly different between the cKO and WT mice at 16 weeks of age. Micro-CT measurements revealed significant gender differences in the trabecular bone volume adjusted for tissue volume at the secondary spongiosa of the femur and the tibia for both genotypes, but no genotype difference was found for any of the trabecular bone measurements of either the femur or the tibia. Trabecular bone volume of distal femur epiphysis was not different between cKO and WT mice. Histology analyses revealed Phd3 cKO mice exhibited a comparable chondrocyte differentiation and proliferation, as evidenced by no changes in cartilage thickness and area in the cKO mice as compared to WT littermates. Consistent with the in vivo data, lentiviral shRNA-mediated knockdown of Phd3 expression in chondrocytes did not affect the expression of markers of chondrocyte differentiation (Col2, Col10, Acan, Sox9). Our study found that Phd2 but not Phd3 expressed in chondrocytes regulates endochondral bone formation, and the compensatory increase in Phd3 expression in the chondrocytes of Phd2 cKO mice is not the cause for increased trabecular bone mass in Phd2 cKO mice. Full article

(This article belongs to the Special Issue Cellular and Molecular Regulation of Bone Remodeling)

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Review

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23 pages, 1446 KiB

Open AccessReview

Regulation of TNF-Induced Osteoclast Differentiation

by Zhenqiang Yao, Stephen J. Getting and Ian C. Locke

Cells 2022, 11(1), 132; https://doi.org/10.3390/cells11010132 - 31 Dec 2021

Cited by 106 | Viewed by 8243

Abstract

Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect. Full article

(This article belongs to the Special Issue Cellular and Molecular Regulation of Bone Remodeling)

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