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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (27 September 2019) | Viewed by 23097

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Prof. Dr. Fredrick M. Pavalko

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Guest Editor

Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
Interests: bone cell biology; mechanotransduction in osteoblasts and osteocytes; mechanical signaling through integrins; mechanical regulation of gene expression in bone; Src kinase function in bone remodeling

Special Issue Information

Dear Colleagues,

This Special Issue on “Osteoblasts and Osteocytes” will cover recent advances in the growing field of skeletal biology that seek to understand the roles of these bone cells in regulating skeletal remodeling. Correct coordination between bone resorption and bone formation is essential for maintaining a healthy skeleton throughout life. Bone-forming osteoblasts that reside on bone surfaces and the osteoctyes that are embedded within bone tissue work together to control the location and rate of bone turnover. Osteocyte networks within bone detect, coordinate, and mediate bone remodeling responses throughout the skeleton in response to different mechanical loads applied to different regions of the skeleton. Among the critical questions being investigated are how these osteocytes embedded within and those on bone surfaces sense and respond to externally applied mechanical loads. Studies seeking to understand the molecular mechanisms of cellular-level detection of various mechanical stimuli including (1) direct tissue strain from loading/bending of bone, and (2) indirect consequence of loading such as load‐induced fluid shear stress over the surfaces of bone are identifying important targets for pharmacologic intervention that can improve skeletal health during aging and skeletal disease. We seek contributions aimed at understanding how bone cells translate a mechanical signal detected at the cell surface into an appropriate sequence of biochemical changes inside the cell that results in a coordinated anabolic or catabolic response. Authors working directly or indirectly on questions related to understanding the cells and molecules and signaling pathways that may contribute to skeletal “mechanosensation” are welcome. Intuitive considerations and abundant experimental evidence support the idea that osteocytes, as the most abundant bone cells, and given their location throughout bone, are the cells most directly responsible for detecting mechanical signals. How these osteocytes work in coordination with bone-resorbing osteoclasts and bone-forming osteoblasts to maintain a healthy skeleton are of great interest to the growing field of skeletal mechanobiology.

Prof. Dr. Fredrick M. Pavalko
Guest Editor

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Keywords

Bone
wnt Signaling
β-catenin
Mechanotransduction
Sclerostin
Skeletal adaptation
Osteoblast
Osteocyte

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Published Papers (6 papers)

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Research

18 pages, 4379 KiB

Open AccessArticle

Effect of Lactoferrin on the Expression Profiles of Long Non-coding RNA during Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells

by Yan Xu, Jing-Jing An, Dina Tabys, Yin-Dan Xie, Tian-Yu Zhao, Hao-Wei Ren and Ning Liu

Int. J. Mol. Sci. 2019, 20(19), 4834; https://doi.org/10.3390/ijms20194834 - 28 Sep 2019

Cited by 21 | Viewed by 3370

Abstract

Lactoferrin (LF) has demonstrated stimulation of osteogenic differentiation of mesenchymal stem cells (MSCs). Long non-coding RNAs (lncRNAs) participate in regulating the osteogenic differentiation processes. However, the impact of LF on lncRNA expression in MSC osteogenic differentiation is poorly understood. Our aim was to investigate the effects of LF on lncRNAs expression profiles, during osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs), by RNA sequencing. A total number of 1331 putative lncRNAs were identified in rBMSCs during osteogenic differentiation in the study. LF influenced the expression of 120 lncRNAs (differentially expressed lncRNAs [DELs], Fold change > 1.5 or < −1.5; p < 0.05) in rBMSCs on day 14 of osteogenic differentiation, consisted of 60 upregulated and 60 down-regulated. Furthermore, the potential functions of DELs were of prediction by searching their target cis- and trans-regulated protein-coding genes. The bioinformatic analysis of DELs target gene revealed that LF led to the disfunction of transforming growth factor beta stimulus (TGF-β) and positive regulation of I-κappa B kinase/NF-κappa B signaling pathway, which may relate to osteogenic differentiation of rBMSCs. Our work is the first profiling of lncRNA in osteogenic differentiation of rBMSCs induced by LF, and provides valuable insights into the potential mechanisms for LF promoting osteogenic activity. Full article

(This article belongs to the Special Issue Osteoblasts and Osteocytes)

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12 pages, 2617 KiB

Open AccessArticle

Twist1 Inactivation in Dmp1-Expressing Cells Increases Bone Mass but Does Not Affect the Anabolic Response to Sclerostin Neutralization

by Karl J. Lewis, Roy B-J Choi, Emily Z. Pemberton, Whitney A. Bullock, Anthony B. Firulli and Alexander G. Robling

Int. J. Mol. Sci. 2019, 20(18), 4427; https://doi.org/10.3390/ijms20184427 - 9 Sep 2019

Cited by 4 | Viewed by 3308

Abstract

Wnt signaling plays a major role in bone metabolism. Advances in our understanding of secreted regulators of Wnt have yielded several therapeutic targets to stimulate osteoanabolism—the most promising of which is the Wnt inhibitor sclerostin. Sclerostin antibody recently gained approval for clinical use to treat osteoporosis, but the biology surrounding sclerostin antagonism is still incompletely understood. Numerous factors regulate the efficacy of sclerostin inhibition on bone formation, a process known as self-regulation. In previous communications we reported that the basic helix-loop-helix transcription factor Twist1—a gene know to regulate skeletal development—is highly upregulated among the osteocyte cell population in mice treated with sclerostin antibody. In this communication, we tested the hypothesis that preventing Twist1 upregulation by deletion of Twist1 from late-stage osteoblasts and osteocytes would increase the efficacy of sclerostin antibody treatment, since Twist1 is known to restrain osteoblast activity in many models. Twist1-floxed loss-of-function mice were crossed to the Dmp1-Cre driver to delete Twist1 in Dmp1-expressing cells. Conditional Twist1 deletion was associated with a mild but significant increase in bone mass, as assessed by dual energy x-ray absorptiometry (DXA) and microCT (µCT) for many endpoints in both male and female mice. Biomechanical properties of the femur were not affected by conditional mutation of Twist1. Sclerostin antibody improved all bone properties significantly, regardless of Twist1 status, sex, or endpoint examined. No interactions were detected when Twist1 status and antibody treatment were examined together, suggesting that Twist1 upregulation in the osteocyte population is not an endogenous mechanism that restrains the osteoanabolic effect of sclerostin antibody treatment. In summary, Twist1 inhibition in the late-stage osteoblast/osteocyte increases bone mass but does not affect the anabolic response to sclerostin neutralization. Full article

(This article belongs to the Special Issue Osteoblasts and Osteocytes)

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17 pages, 4230 KiB

Open AccessArticle

Quality Analysis of Minerals Formed by Jaw Periosteal Cells under Different Culture Conditions

by Marina Danalache, Sophie-Maria Kliesch, Marita Munz, Andreas Naros, Siegmar Reinert and Dorothea Alexander

Int. J. Mol. Sci. 2019, 20(17), 4193; https://doi.org/10.3390/ijms20174193 - 27 Aug 2019

Cited by 9 | Viewed by 3172

Abstract

Previously, we detected a higher degree of mineralization in fetal calf serum (FCS) compared to serum-free cultured jaw periosteum derived osteoprogenitor cells (JPCs). By Raman spectroscopy, we detected an earlier formation of mineralized extracellular matrix (ECM) of higher quality under serum-free media conditions. However, mineralization potential remained too low. In the present study, we aimed to investigate the biochemical composition and subsequent biomechanical properties of the JPC-formed ECM and minerals under human platelet lysate (hPL) and FCS supplementation. JPCs were isolated (n = 4 donors) and expanded under FCS conditions and used in passage five for osteogenic induction under both, FCS and hPL media supplementation. Raman spectroscopy and Alizarin Red/von Kossa staining were employed for biochemical composition analyses and for visualization and quantification of mineralization. Osteocalcin gene expression was analyzed by quantitative PCR. Biomechanical properties were assessed by using atomic force microscopy (AFM). Raman spectroscopic measurements showed significantly higher (p < 0.001) phosphate to protein ratios and in the tendency, lower carbonate to phosphate ratios in osteogenically induced JPCs under hPL in comparison to FCS culturing. Furthermore, higher crystal sizes were detected under hPL culturing of the cells. With respect to the ECM, significantly higher ratios of the precursor protein proline to hydroxyproline were detected in hPL-cultured JPC monolayers (p < 0.001). Additionally, significantly higher levels (p < 0.001) of collagen cross-linking were calculated, indicating a higher degree of collagen maturation in hPL-cultured JPCs. By atomic force microscopy, a significant increase in ECM stiffness (p < 0.001) of FCS cultured JPC monolayers was observed. The reverse effect was measured for the JPC formed precipitates/minerals. Under hPL supplementation, JPCs formed minerals of significantly higher stiffness (p < 0.001) when compared to the FCS setting. This study demonstrates that hPL culturing of JPCs leads to the formation of an anorganic material of superior quality in terms of biochemical composition and mechanical properties. Full article

(This article belongs to the Special Issue Osteoblasts and Osteocytes)

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14 pages, 1445 KiB

Open AccessArticle

Activation of TGF-β Canonical and Noncanonical Signaling in Bovine Lactoferrin-Induced Osteogenic Activity of C3H10T1/2 Mesenchymal Stem Cells

by Yixuan Li, Wei Zhang, Fazheng Ren and Huiyuan Guo

Int. J. Mol. Sci. 2019, 20(12), 2880; https://doi.org/10.3390/ijms20122880 - 13 Jun 2019

Cited by 15 | Viewed by 3508

Abstract

Lactoferrin (LF) is known to modulate the bone anabolic effect. Previously, we and others reported that the effects of LF on the bone may be conferred by the stimulation of transforming growth factor β (TGF-β) signaling in the preosteoblast. However, the underlying molecular mechanisms of LF-induced osteogenic differentiation of mesenchymal stem cells (MSCs) has not been identified. In this study, we tested the hypothesis that the effects of LF on osteogenesis of MSCs required mediation by TGF-β Receptors and activating TGF-β signaling pathway. Using siRNA silencing technology, the knockdown of TGF-β Receptor II (TβRII) could significantly attenuate LF’s effect on the proliferation rate and alkaline phosphatase (ALP) activity of MSCs. It indicated that LF induced osteogenic activity that is dependent on TβRII in C3H10T1/2. Subsequently, it was shown that LF activated Smad2. Downregulating TGF-β Receptor I (TβRI) with SB431542 attenuated the expression of p-Smad2 and p-P38, also the LF-induced the osteogenic activity. Besides, the stimulation by LF on the expression of Osteocalcin (OCN), Osteopontin (OPN), Collagen-2a1 (Col2a1), and Fibroblast Growth Factor 2 (FGF2) were abolished by SB431542. These results confirmed that LF induced osteogenic activity though the TGF-β canonical and noncanonical signaling pathway. This study provided the first evidence of the signaling mechanisms of LF’s effect on osteogenesis in MSCs. Full article

(This article belongs to the Special Issue Osteoblasts and Osteocytes)

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13 pages, 7279 KiB

Open AccessArticle

Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6/RANKL Axis

by Hyung Joon Kim, Ha Jin Kim, YunJeong Choi, Moon-Kyoung Bae, Dae Seok Hwang, Sang-Hun Shin and Jae-Yeol Lee

Int. J. Mol. Sci. 2019, 20(6), 1467; https://doi.org/10.3390/ijms20061467 - 22 Mar 2019

Cited by 33 | Viewed by 4768

Abstract

Bisphosphonates are one of the most widely used synthetic pyrophosphate analogues for the treatment of bone resorbing diseases such as osteoporosis, multiple myeloma, and bone metastases. Although the therapeutic usefulness of bisphosphonates mainly depends on their anti-osteoclastogenic effect, a severe side-effect of bisphosphonates called bisphosphonate-related osteonecrosis of the jaw (BRONJ) could not be explained by the anti-osteoclastogenic effect of bisphosphonates. In the present study, we have evaluated the changes in osteoclastogenesis- or osteoblastogenesis-supporting activities of osteocytes induced by bisphosphonates. Zoledronate, a nitrogen-containing bisphosphonate, markedly increased both the receptor activator of nuclear factor kB ligand (RANKL) as well as sclerostin in osteocyte-like MLO-Y4 cells, which were functionally revalidated by osteoclast/osteoblast generating activities of the conditioned medium obtained from zoledronate-treated MLO-Y4 cells. Of note, the zoledronate treatment-induced upregulation of the RANKL expression was mediated by autocrine interleukin-6 (IL-6) and subsequent activation of the signal transducer and activator of transcription 3 (STAT3) pathway. These results were evidenced by the blunted RANKL expression in the presence of a Janus activated kinase (JAK2)/STAT3 inhibitor, AG490. Also, the osteoclastogenesis-supporting activity was significantly decreased in zoledronate-treated MLO-Y4 cells in the presence of IL-6 neutralizing IgG compared to that of the control IgG. Thus, our results show previously unanticipated effects of anti-bone resorptive bisphosphonate and suggest a potential clinical importance of osteocytes in BRONJ development. Full article

(This article belongs to the Special Issue Osteoblasts and Osteocytes)

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15 pages, 3037 KiB

Open AccessArticle

Alpha-5 Integrin Mediates Simvastatin-Induced Osteogenesis of Bone Marrow Mesenchymal Stem Cells

by Pei-Lin Shao, Shun-Cheng Wu, Zih-Yin Lin, Mei-Ling Ho, Chung-Hwan Chen and Chau-Zen Wang

Int. J. Mol. Sci. 2019, 20(3), 506; https://doi.org/10.3390/ijms20030506 - 24 Jan 2019

Cited by 27 | Viewed by 4337

Abstract

Simvastatin (SVS) promotes the osteogenic differentiation of mesenchymal stem cells (MSCs) and has been studied for MSC-based bone regeneration. However, the mechanism underlying SVS-induced osteogenesis is not well understood. We hypothesize that α5 integrin mediates SVS-induced osteogenic differentiation. Bone marrow MSCs (BMSCs) derived from BALB/C mice, referred to as D1 cells, were used. Alizarin red S (calcium deposition) and alkaline phosphatase (ALP) staining were used to evaluate SVS-induced osteogenesis of D1 cells. The mRNA expression levels of α5 integrin and osteogenic marker genes (bone morphogenetic protein-2 (BMP-2), runt-related transcription factor 2 (Runx2), collagen type I, ALP and osteocalcin (OC)) were detected using quantitative real-time PCR. Surface-expressed α5 integrin was detected using flow cytometry analysis. Protein expression levels of α5 integrin and phosphorylated focal adhesion kinase (p-FAK), which is downstream of α5 integrin, were detected using Western blotting. siRNA was used to deplete the expression of α5 integrin in D1 cells. The results showed that SVS dose-dependently enhanced the gene expression levels of osteogenic marker genes as well as subsequent ALP activity and calcium deposition in D1 cells. Upregulated p-FAK was accompanied by an increased protein expression level of α5 integrin after SVS treatment. Surface-expressed α5 integrin was also upregulated after SVS treatment. Depletion of α5 integrin expression significantly suppressed SVS-induced osteogenic gene expression levels, ALP activity, and calcium deposition in D1 cells. These results identify a critical role of α5 integrin in SVS-induced osteogenic differentiation of BMSCs, which may suggest a therapeutic strategy to modulate α5 integrin/FAK signaling to promote MSC-based bone regeneration. Full article

(This article belongs to the Special Issue Osteoblasts and Osteocytes)

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