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15 pages, 2389 KiB

Open AccessArticle

Runx2 Regulates Galnt3 and Fgf23 Expressions and Galnt3 Decelerates Osteoid Mineralization by Stabilizing Fgf23

by Qing Jiang, Xin Qin, Takeshi Moriishi, Ryo Fukuyama, Shinichi Katsumata, Hiroshi Matsuzaki, Hisato Komori, Yuki Matsuo, Chiharu Sakane, Kosei Ito, Hironori Hojo, Shinsuke Ohba and Toshihisa Komori

Int. J. Mol. Sci. 2024, 25(4), 2275; https://doi.org/10.3390/ijms25042275 - 14 Feb 2024

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Abstract

Runx2 (runt related transcription factor 2) is an essential transcription factor for osteoblast proliferation and differentiation. Uridine diphosphate (UDP)-N-acetylgalactosamine (GalNAc): polypeptide GalNAc-transferase 3 (Galnt3) prevents proteolytic processing of fibroblast growth factor 23 (Fgf23), which is a hormone that regulates the serum level of [...] Read more.

Runx2 (runt related transcription factor 2) is an essential transcription factor for osteoblast proliferation and differentiation. Uridine diphosphate (UDP)-N-acetylgalactosamine (GalNAc): polypeptide GalNAc-transferase 3 (Galnt3) prevents proteolytic processing of fibroblast growth factor 23 (Fgf23), which is a hormone that regulates the serum level of phosphorus. Runx2 and Galnt3 were expressed in osteoblasts and osteocytes, and Fgf23 expression was restricted to osteocytes in bone. Overexpression and knock-down of Runx2 upregulated and downregulated, respectively, the expressions of Galnt3 and Fgf23, and Runx2 directly regulated the transcriptional activity of Galnt3 in reporter assays. The expressions of Galnt3 and Fgf23 in osteoblast-specific Runx2 knockout (Runx2^fl/flCre) mice were about half those in Runx2^fl/fl mice. However, the serum levels of phosphorus and intact Fgf23 in Runx2^fl/flCre mice were similar to those in Runx2^fl/fl mice. The trabecular bone volume was increased during aging in both male and female Galnt3^−/− mice, but the osteoid was reduced. The markers for bone formation and resorption in Galnt3^−/− mice were similar to the control in both sexes. Galnt3^−/− mice exhibited hyperphosphatemia and hypercalcemia, and the intact Fgf23 was about 40% that of wild-type mice. These findings indicated that Runx2 regulates the expressions of Galnt3 and Fgf23 and that Galnt3 decelerates the mineralization of osteoid by stabilizing Fgf23. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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16 pages, 4886 KiB

Open AccessArticle

Combined Transcriptomics and Metabolomics Identify Regulatory Mechanisms of Porcine Vertebral Chondrocyte Development In Vitro

by Mingming Xue, Ning Huang, Yabiao Luo, Xiaoyang Yang, Yubei Wang and Meiying Fang

Int. J. Mol. Sci. 2024, 25(2), 1189; https://doi.org/10.3390/ijms25021189 - 18 Jan 2024

Cited by 2 | Viewed by 867

Abstract

Porcine body length is closely related to meat production, growth, and reproductive performance, thus playing a key role in the profitability of the pork industry. Cartilage development is critical to longitudinal elongation of individual vertebrae. This study isolated primary porcine vertebral chondrocytes (PVCs) [...] Read more.

Porcine body length is closely related to meat production, growth, and reproductive performance, thus playing a key role in the profitability of the pork industry. Cartilage development is critical to longitudinal elongation of individual vertebrae. This study isolated primary porcine vertebral chondrocytes (PVCs) to clarify the complex mechanisms of elongation. We used transcriptome and target energy metabolome technologies to confirm crucial genes and metabolites in primary PVCs at different differentiation stages (0, 4, 8, and 12 days). Pairwise comparisons of the four stages identified 4566 differentially expressed genes (DEGs). Time-series gene cluster and functional analyses of these DEGs revealed four clusters related to metabolic processes, cartilage development, vascular development, and cell cycle regulation. We constructed a transcriptional regulatory network determining chondrocyte maturation. The network indicated that significantly enriched transcription factor (TF) families, including zf-C2H2, homeobox, TF_bZIP, and RHD, are important in cell cycle and differentiation processes. Further, dynamic network biomarker (DNB) analysis revealed that day 4 was the tipping point for chondrocyte development, consistent with morphological and metabolic changes. We found 24 DNB DEGs, including the TFs NFATC2 and SP7. Targeted energy metabolome analysis showed that most metabolites were elevated throughout chondrocyte development; notably, 16 differentially regulated metabolites (DRMs) were increased at three time points after cell differentiation. In conclusion, integrated metabolome and transcriptome analyses highlighted the importance of amino acid biosynthesis in chondrocyte development, with coordinated regulation of DEGs and DRMs promoting PVC differentiation via glucose oxidation. These findings reveal the regulatory mechanisms underlying PVC development and provide an important theoretical reference for improving pork production. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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15 pages, 3792 KiB

Open AccessArticle

Bcl2l1 Deficiency in Osteoblasts Reduces the Trabecular Bone Due to Enhanced Osteoclastogenesis Likely through Osteoblast Apoptosis

by Takeshi Moriishi, Yosuke Kawai, Ryo Fukuyama, Yuki Matsuo, You-Wen He, Haruhiko Akiyama, Izumi Asahina and Toshihisa Komori

Int. J. Mol. Sci. 2023, 24(24), 17319; https://doi.org/10.3390/ijms242417319 - 10 Dec 2023

Cited by 1 | Viewed by 859

Abstract

Bcl2l1 (Bcl-XL) belongs to the Bcl-2 family, Bcl2 and Bcl2-XL are major anti-apoptotic proteins, and the apoptosis of osteoblasts is a key event for bone homeostasis. As the functions of Bcl2l1 in osteoblasts and bone homeostasis remain unclear, we generated osteoblast-specific Bcl2l1-deficient [...] Read more.

Bcl2l1 (Bcl-XL) belongs to the Bcl-2 family, Bcl2 and Bcl2-XL are major anti-apoptotic proteins, and the apoptosis of osteoblasts is a key event for bone homeostasis. As the functions of Bcl2l1 in osteoblasts and bone homeostasis remain unclear, we generated osteoblast-specific Bcl2l1-deficient (Bcl2l1^fl/flCre) mice using 2.3-kb Col1a1 Cre. Trabecular bone volume and the trabecular number were lower in Bcl2l1^fl/flCre mice of both sexes than in Bcl2l1^fl/fl mice. In bone histomorphometric analysis, osteoclast parameters were increased in Bcl2l1^fl/flCre mice, whereas osteoblast parameters and the bone formation rate were similar to those in Bcl2l1^fl/fl mice. TUNEL-positive osteoblastic cells and serum TRAP5b levels were increased in Bcl2l1^fl/flCre mice. The deletion of Bcl2l1 in osteoblasts induced Tnfsf11 expression, whereas the overexpression of Bcl-XL had no effect. In a co-culture of Bcl2l1-deficient primary osteoblasts and wild-type bone-marrow-derived monocyte/macrophage lineage cells, the numbers of multinucleated TRAP-positive cells and resorption pits increased. Furthermore, serum deprivation or the deletion of Bcl2l1 in primary osteoblasts increased apoptosis and ATP levels in the medium. Therefore, the reduction in trabecular bone in Bcl2l1^fl/flCre mice may be due to enhanced bone resorption through osteoblast apoptosis and the release of ATP from apoptotic osteoblasts, and Bcl2l1 may inhibit bone resorption by preventing osteoblast apoptosis. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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16 pages, 3470 KiB

Open AccessArticle

B. abortus Infection Promotes an Imbalance in the Adipocyte–Osteoblast Crosstalk Favoring Bone Resorption

by Rosa Nicole Freiberger, Cinthya Alicia Marcela López, Franco Agustín Sviercz, Cintia Cevallos, Alex David Guano, Patricio Jarmoluk, Jorge Quarleri and María Victoria Delpino

Int. J. Mol. Sci. 2023, 24(6), 5617; https://doi.org/10.3390/ijms24065617 - 15 Mar 2023

Cited by 2 | Viewed by 1420

Abstract

Osteoarticular injury is the most common presentation of active brucellosis in humans. Osteoblasts and adipocytes originate from mesenchymal stem cells (MSC). Since those osteoblasts are bone-forming cells, the predilection of MSC to differentiate into adipocytes or osteoblasts is a potential factor involved in [...] Read more.

Osteoarticular injury is the most common presentation of active brucellosis in humans. Osteoblasts and adipocytes originate from mesenchymal stem cells (MSC). Since those osteoblasts are bone-forming cells, the predilection of MSC to differentiate into adipocytes or osteoblasts is a potential factor involved in bone loss. In addition, osteoblasts and adipocytes can be converted into each other according to the surrounding microenvironment. Here, we study the incumbency of B. abortus infection in the crosstalk between adipocytes and osteoblasts during differentiation from its precursors. Our results indicate that soluble mediators present in culture supernatants from B. abotus-infected adipocytes inhibit osteoblast mineral matrix deposition in a mechanism dependent on the presence of IL-6 with the concomitant reduction of Runt-related transcription factor 2 (RUNX-2) transcription, but without altering organic matrix deposition and inducing nuclear receptor activator ligand kβ (RANKL) expression. Secondly, B. abortus-infected osteoblasts stimulate adipocyte differentiation with the induction of peroxisome proliferator-activated receptor γ (PPAR-γ) and CCAAT enhancer binding protein β (C/EBP-β). We conclude that adipocyte–osteoblast crosstalk during B. abortus infection could modulate mutual differentiation from its precursor cells, contributing to bone resorption. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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12 pages, 2780 KiB

Open AccessArticle

PPP3R1 Promotes MSCs Senescence by Inducing Plasma Membrane Depolarization and Increasing Ca²⁺ Influx

by Molin Li, Weimin Gong, Jie Chen, Yining Zhang, Yufei Ma and Xiaolin Tu

Int. J. Mol. Sci. 2023, 24(5), 4421; https://doi.org/10.3390/ijms24054421 - 23 Feb 2023

Cited by 1 | Viewed by 1678

Abstract

Aging of mesenchymal stem cells(MSCs) has been widely reported to be strongly associated with aging-related diseases, including osteoporosis (OP). In particular, the beneficial functions of mesenchymal stem cells decline with age, limiting their therapeutic efficacy in age-related bone loss diseases. Therefore, how to [...] Read more.

Aging of mesenchymal stem cells(MSCs) has been widely reported to be strongly associated with aging-related diseases, including osteoporosis (OP). In particular, the beneficial functions of mesenchymal stem cells decline with age, limiting their therapeutic efficacy in age-related bone loss diseases. Therefore, how to improve mesenchymal stem cell aging to treat age-related bone loss is the current research focus. However, the underlying mechanism remains unclear. In this study, protein phosphatase 3, regulatory subunit B, alpha isoform, calcineurin B, type I (PPP3R1) was found to accelerate the senescence of mesenchymal stem cells, resulting in reduced osteogenic differentiation and enhanced adipogenic differentiation in vitro. Mechanistically, PPP3R1 induces changes in membrane potential to promote cellular senescence by polarizing to depolarizing, increasing Ca²⁺ influx and activating downstream NFAT/ATF3/p53 signaling. In conclusion, the results identify a novel pathway of mesenchymal stem cell aging that may lead to novel therapeutic approaches for age-related bone loss. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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22 pages, 5249 KiB

Open AccessArticle

Protocol for Cell Colonization and Comprehensive Monitoring of Osteogenic Differentiation in 3D Scaffolds Using Biochemical Assays and Multiphoton Imaging

by Kai Peter Sommer, Adrian Krolinski, Mohammad Mirkhalaf, Hala Zreiqat, Oliver Friedrich and Martin Vielreicher

Int. J. Mol. Sci. 2023, 24(3), 2999; https://doi.org/10.3390/ijms24032999 - 3 Feb 2023

Cited by 2 | Viewed by 2079

Abstract

The goal of bone tissue engineering is to build artificial bone tissue with properties that closely resemble human bone and thereby support the optimal integration of the constructs (biografts) into the body. The development of tissues in 3D scaffolds includes several complex steps [...] Read more.

The goal of bone tissue engineering is to build artificial bone tissue with properties that closely resemble human bone and thereby support the optimal integration of the constructs (biografts) into the body. The development of tissues in 3D scaffolds includes several complex steps that need to be optimized and monitored. In particular, cell–material interaction during seeding, cell proliferation and cell differentiation within the scaffold pores play a key role. In this work, we seeded two types of 3D-printed scaffolds with pre-osteoblastic MC3T3-E1 cells, proliferated and differentiated the cells, before testing and adapting different assays and imaging methods to monitor these processes. Alpha-TCP/HA (α-TCP with low calcium hydroxyapatite) and baghdadite (Ca₃ZrSi₂O₉) scaffolds were used, which had comparable porosity (~50%) and pore sizes (~300–400 µm). Cell adhesion to both scaffolds showed ~95% seeding efficiency. Cell proliferation tests provided characteristic progression curves over time and increased values for α-TCP/HA. Transmitted light imaging displayed a homogeneous population of scaffold pores and allowed us to track their opening state for the supply of the inner scaffold regions by diffusion. Fluorescence labeling enabled us to image the arrangement and morphology of the cells within the pores. During three weeks of osteogenesis, ALP activity increased sharply in both scaffolds, but was again markedly increased in α-TCP/HA scaffolds. Multiphoton SHG and autofluorescence imaging were used to investigate the distribution, morphology, and arrangement of cells; collagen-I fiber networks; and hydroxyapatite crystals. The collagen-I networks became denser and more structured during osteogenic differentiation and appeared comparable in both scaffolds. However, imaging of the HA crystals showed a different morphology between the two scaffolds and appeared to arrange in the α-TCP/HA scaffolds along collagen-I fibers. ALP activity and SHG imaging indicated a pronounced osteo-inductive effect of baghdadite. This study describes a series of methods, in particular multiphoton imaging and complementary biochemical assays, to validly measure and track the development of bone tissue in 3D scaffolds. The results contribute to the understanding of cell colonization, growth, and differentiation, emphasizing the importance of optimal media supply of the inner scaffold regions. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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15 pages, 2911 KiB

Open AccessArticle

Lumican, an Exerkine, Protects against Skeletal Muscle Loss

by Han Jin Cho, Young-Sun Lee, Da Ae Kim, Sung Ah Moon, Seung Eun Lee, Seung Hun Lee and Jung-Min Koh

Int. J. Mol. Sci. 2022, 23(17), 10031; https://doi.org/10.3390/ijms231710031 - 2 Sep 2022

Cited by 4 | Viewed by 1676

Abstract

Exerkines are soluble factors secreted by exercised muscles, mimicking the effects of exercise in various organs, including the muscle itself. Lumican is reportedly secreted from muscles; however, its roles in skeletal muscle remain unknown. Herein, we found that lumican mRNA expression in the [...] Read more.

Exerkines are soluble factors secreted by exercised muscles, mimicking the effects of exercise in various organs, including the muscle itself. Lumican is reportedly secreted from muscles; however, its roles in skeletal muscle remain unknown. Herein, we found that lumican mRNA expression in the extensor digitorum longus was significantly higher in exercised mice than in unloading mice, and lumican stimulated myogenesis in vitro. Additionally, lumican knockdown significantly decreased muscle mass and cross-sectional area (CSA) of the muscle fiber in the gastrocnemius muscle of exercised mice. Lumican upregulated phosphorylation of p38 mitogen-activated protein kinase (MAPK) and a p38 inhibitor near completely blocked lumican-stimulated myogenesis. Inhibitors for integrin α2β1 and integrin ανβ3 also prevented lumican-stimulated myogenesis. Systemic lumican treatment, administered via the tail vein for 4 weeks, significantly increased relative muscle masses by 36.1% in ovariectomized mice. In addition, intramuscular lumican injection into unloaded muscles for 2 weeks significantly increased muscle mass by 8.5%. Both intravenous and intramuscular lumican treatment significantly increased muscle CSA. Our in vitro and in vivo experiments indicate that lumican is a muscle-secreted exerkine that affords protection against muscle loss by activating p38 MAPK via integrin receptors. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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15 pages, 2030 KiB

Open AccessArticle

The Kinesin Gene KIF26B Modulates the Severity of Post-Traumatic Heterotopic Ossification

by George A. E. Pickering, Favour Felix-Ilemhenbhio, Matthew J. Clark, Klaudia Kocsy, Jonathan Simpson, Ilaria Bellantuono, Alison Gartland, Jeremy Mark Wilkinson, Konstantinos Hatzikotoulas and Endre Kiss-Toth

Int. J. Mol. Sci. 2022, 23(16), 9203; https://doi.org/10.3390/ijms23169203 - 16 Aug 2022

Viewed by 1986

Abstract

The formation of pathological bone deposits within soft tissues, termed heterotopic ossification (HO), is common after trauma. However, the severity of HO formation varies substantially between individuals, from relatively isolated small bone islands through to extensive soft tissue replacement by bone giving rise [...] Read more.

The formation of pathological bone deposits within soft tissues, termed heterotopic ossification (HO), is common after trauma. However, the severity of HO formation varies substantially between individuals, from relatively isolated small bone islands through to extensive soft tissue replacement by bone giving rise to debilitating symptoms. The aim of this study was to identify novel candidate therapeutic molecular targets for severe HO. We conducted a genome-wide scan in men and women with HO of varying severity following hip replacement for osteoarthritis. HO severity was dichotomized as mild or severe, and association analysis was performed with adjustment for age and sex. We next confirmed expression of the gene encoded by the lead signal in human bone and in primary human mesenchymal stem cells. We then examined the effect of gene knockout in a murine model of osseous trans-differentiation, and finally we explored transcription factor phosphorylation in key pathways perturbed by the gene. Ten independent signals were suggestively associated with HO severity, with KIF26B as the lead. We subsequently confirmed KIF26B expression in human bone and upregulation upon BMP2-induced osteogenic differentiation in primary human mesenchymal stem cells, and also in a rat tendo-Achilles model of post-traumatic HO. CRISPR-Cas9 mediated knockout of Kif26b inhibited BMP2-induced Runx2, Sp7/Osterix, Col1A1, Alp, and Bglap/Osteocalcin expression and mineralized nodule formation in a murine myocyte model of osteogenic trans-differentiation. Finally, KIF26B deficiency inhibited ERK MAP kinase activation during osteogenesis, whilst augmenting p38 and SMAD 1/5/8 phosphorylation. Taken together, these data suggest a role for KIF26B in modulating the severity of post-traumatic HO and provide a potential novel avenue for therapeutic translation. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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Review

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20 pages, 1101 KiB

Open AccessReview

Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair

by Wenjing Xu, Yumei Yang, Na Li and Jinlian Hua

Int. J. Mol. Sci. 2023, 24(19), 14484; https://doi.org/10.3390/ijms241914484 - 23 Sep 2023

Cited by 4 | Viewed by 1466

Abstract

Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms [...] Read more.

Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms by which immune cells and their cytokines are regulated in bone healing remain unclear. The use of mesenchymal stem cells (MSCs) for cellular therapy of bone injuries is a novel clinical treatment approach. Bone progenitor MSCs not only differentiate into bone, but also interact with the immune system to promote the healing process. We review in vitro and in vivo studies on the role of the immune system and bone marrow MSCs in bone healing and their interactions. A deeper understanding of this paradigm may provide clues to potential therapeutic targets in the healing process, thereby improving the reliability and safety of clinical applications of MSCs to promote bone healing. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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34 pages, 2391 KiB

Open AccessReview

Prospects and Advances in Adoptive Natural Killer Cell Therapy for Unmet Therapeutic Needs in Pediatric Bone Sarcomas

by Halin Bareke, Adrián Ibáñez-Navarro, Pilar Guerra-García, Carlos González Pérez, Pedro Rubio-Aparicio, Diego Plaza López de Sabando, Ana Sastre-Urgelles, Eduardo José Ortiz-Cruz and Antonio Pérez-Martínez

Int. J. Mol. Sci. 2023, 24(9), 8324; https://doi.org/10.3390/ijms24098324 - 5 May 2023

Viewed by 2654

Abstract

Malignant bone tumors are aggressive tumors, with a high tendency to metastasize, that are observed most frequently in adolescents during rapid growth spurts. Pediatric patients with malignant bone sarcomas, Ewing sarcoma and osteosarcoma, who present with progressive disease have dire survival rates despite [...] Read more.

Malignant bone tumors are aggressive tumors, with a high tendency to metastasize, that are observed most frequently in adolescents during rapid growth spurts. Pediatric patients with malignant bone sarcomas, Ewing sarcoma and osteosarcoma, who present with progressive disease have dire survival rates despite aggressive therapy. These therapies can have long-term effects on bone growth, such as decreased bone mineral density and reduced longitudinal growth. New therapeutic approaches are therefore urgently needed for targeting pediatric malignant bone tumors. Harnessing the power of the immune system against cancer has improved the survival rates dramatically in certain cancer types. Natural killer (NK) cells are a heterogeneous group of innate effector cells that possess numerous antitumor effects, such as cytolysis and cytokine production. Pediatric sarcoma cells have been shown to be especially susceptible to NK-cell-mediated killing. NK-cell adoptive therapy confers numerous advantages over T-cell adoptive therapy, including a good safety profile and a lack of major histocompatibility complex restriction. NK-cell immunotherapy has the potential to be a new therapy for pediatric malignant bone tumors. In this manuscript, we review the general characteristics of osteosarcoma and Ewing sarcoma, discuss the long-term effects of sarcoma treatment on bones, and the barriers to effective immunotherapy in bone sarcomas. We then present the laboratory and clinical studies on NK-cell immunotherapy for pediatric malignant bone tumors. We discuss the various donor sources and NK-cell types, the engineering of NK cells and combinatorial treatment approaches that are being studied to overcome the current challenges in adoptive NK-cell therapy, while suggesting approaches for future studies on NK-cell immunotherapy in pediatric bone tumors. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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20 pages, 423 KiB

Open AccessReview

Mouse Models of Mineral Bone Disorders Associated with Chronic Kidney Disease

by Ariane Zaloszyc, Julie Bernardor, Justine Bacchetta, Gilles Laverny and Claus Peter Schmitt

Int. J. Mol. Sci. 2023, 24(6), 5325; https://doi.org/10.3390/ijms24065325 - 10 Mar 2023

Cited by 1 | Viewed by 1577

Abstract

Patients with chronic kidney disease (CKD) inevitably develop mineral and bone disorders (CKD–MBD), which negatively impact their survival and quality of life. For a better understanding of underlying pathophysiology and identification of novel therapeutic approaches, mouse models are essential. CKD can be induced [...] Read more.

Patients with chronic kidney disease (CKD) inevitably develop mineral and bone disorders (CKD–MBD), which negatively impact their survival and quality of life. For a better understanding of underlying pathophysiology and identification of novel therapeutic approaches, mouse models are essential. CKD can be induced by surgical reduction of a functional kidney mass, by nephrotoxic compounds and by genetic engineering specifically interfering with kidney development. These models develop a large range of bone diseases, recapitulating different types of human CKD–MBD and associated sequelae, including vascular calcifications. Bones are usually studied by quantitative histomorphometry, immunohistochemistry and micro-CT, but alternative strategies have emerged, such as longitudinal in vivo osteoblast activity quantification by tracer scintigraphy. The results gained from the CKD–MBD mouse models are consistent with clinical observations and have provided significant knowledge on specific pathomechanisms, bone properties and potential novel therapeutic strategies. This review discusses available mouse models to study bone disease in CKD. Full article

(This article belongs to the Special Issue Bone Development and Growth 2.0)

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