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Tu Y, Li Y, Qu G, Ning Y, Li B, Li G, Wu M, Li S, Huang Y. A Review of Basic Fibroblast Growth Factor Delivery Strategies and Applications in Regenerative Medicine. J Biomed Mater Res A 2025; 113:e37834. [PMID: 39740125 DOI: 10.1002/jbm.a.37834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/24/2024] [Accepted: 10/26/2024] [Indexed: 01/02/2025]
Abstract
Basic fibroblast growth factor (bFGF) is a significant member of the fibroblast growth factor (FGF) family. The bFGF has a three-dimensional structure comprising 12 reverse parallel β-folds. This structure facilitates tissue wound repair, angiogenesis, bone formation, cartilage repair, and nerve regeneration. Consequently, it has garnered significant attention from scholars both domestically and internationally. However, the instability and degradation properties of bFGF in vivo have limited its clinical application. Significant interest has arisen in the development of novel bFGF delivery systems that can address the shortcomings of bFGF and enhance its bioavailability by controlling the release amount, timing, and location. This article offers a comprehensive overview of the research and recent advances in various bFGF delivery systems, including hydrogels, liposomes, microspheres, and nanoparticles. Subsequently, the applications of bFGF pharmaceutical preparations in various fields are described. Finally, the current clinical applications of bFGF drug formulations and those in clinical trials are discussed, along with their clinical translation and future trends.
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Affiliation(s)
- Yuhan Tu
- Department of Pharmacy, Yueqing Third People's Hospital, Wenzhou, China
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Yang Li
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Gaoer Qu
- Department of Pharmacy, Yueqing Third People's Hospital, Wenzhou, China
| | - Yangyang Ning
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Bin Li
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Guoben Li
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Min Wu
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Shijun Li
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Yangge Huang
- Department of Pharmacy, Yueqing Third People's Hospital, Wenzhou, China
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2
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Agas D, Gabai V, Sufianov AA, Shneider A, Giovanna Sabbieti M. P62/SQSTM1 enhances osteogenesis and attenuates inflammatory signals in bone marrow microenvironment. Gen Comp Endocrinol 2022; 320:114009. [PMID: 35227727 DOI: 10.1016/j.ygcen.2022.114009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 11/04/2022]
Abstract
Bone marrow-derived mesenchymal/stromal stem cells (MSCs) became a major focus of research since the anti-inflammatory features and the osteogenic commitment of these cells can prevent the inflamm-aging and various form of osteopenia in humans and animals. We previously showed that p62/SQSTM1 plasmid can prompt release of anti-inflammatory cytokines/chemokines by MSC when injected in adult mice. Furthermore, it can enhance osteoblastogenesis at the expense of adipogenesis and ameliorate bone density and bone remodeling. On the other hand, absence of p62 partially exhausted MSC pool caused expansion of fat cells within bone marrow and pro-inflammatory mediator's accumulation. Given the critical function of p62 as molecular hub of MSC dynamics, here, using MSCs from p62 knockout adult mice, we investigated the effect of this protein on MSC survival and bone-forming molecule cascades. We found that the main osteogenic routes are impaired in absence of p62. In particular, lack of p62 can suppress Smads activation, and Osterix and CREBs expression, thus significantly modifying the schedule of MSCs differentiation. MSCs obtained from p62-/- mice have also demonstrate an amplified NFκB/ Smad1/5/8 colocalization along with NFκB activation in the nucleus, which precludes Smads binding to target promoters. Considering the "teamwork" of TGFβ, PTH and BMP2 on MSC homeostatic behavior, we consider that p62 exerts an essential role as a hub protein. Lastly, ex vivo pulsing p62-deficient MSCs, which then will be administered to a patient as a cell therapy, may be considered as a treatment for bone and bone marrow disorders.
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Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, (MC), Italy.
| | | | - Albert A Sufianov
- Federal Center of Neurosurgery, Tyumen, Russian Federation; Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Alexander Shneider
- CureLab Oncology Inc, Dedham, MA, USA; Ariel University, Department of Molecular Biology, Israel; Peter the Great St. Petersburg Polytechnic University, Institute of Biomedical Systems and Biotechnology, Russian Federation
| | - Maria Giovanna Sabbieti
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, (MC), Italy.
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3
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Parathyroid hormone (PTH) regulation of metabolic homeostasis: An old dog teaches us new tricks. Mol Metab 2022; 60:101480. [PMID: 35338013 PMCID: PMC8980887 DOI: 10.1016/j.molmet.2022.101480] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/11/2022] [Accepted: 03/16/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Late in the nineteenth century, it was theorized that a circulating product produced by the parathyroid glands could negatively impact skeletal homeostasis. A century later, intermittent administration of that protein, namely parathyroid hormone (PTH), was approved by the FDA and EMA as the first anabolic agent to treat osteoporosis. Yet, several unanswered but important questions remain about the skeletal actions of PTH. SCOPE OF REVIEW Current research efforts have focused on improving the efficacy of PTH treatment by designing structural analogs and identifying other targets (e.g., the PTH or the calcium sensing receptor). A unique but only recently described aspect of PTH action is its regulation of cellular bioenergetics and metabolism, namely in bone and adipose tissue but also in other tissues. The current review aims to provide a brief background on PTH's previously described actions on bone and highlights how PTH regulates osteoblast bioenergetics, contributing to greater bone formation. It will also shed light on how PTH could alter metabolic homeostasis through its actions in other cells and tissues, thereby impacting the skeleton in a cell non-autonomous manner. MAJOR CONCLUSIONS PTH administration enhances bone formation by targeting the osteoblast through transcriptional changes in several pathways; the most prominent is via adenyl cyclase and PKA. PTH and its related protein, PTHrP, also induce glycolysis and fatty acid oxidation in bone cells and drive lipolysis and thermogenic programming in adipocytes; the latter may indirectly but positively influence skeletal metabolism. While much work remains, alterations in cellular metabolism may also provide a novel mechanism related to PTH's temporal actions. Thus, the bioenergetic impact of PTH can be considered another of the myriad anabolic effects of PTH on the skeleton. Just as importantly from a translational perspective, the non-skeletal metabolic effects may lead to a better understanding of whole-body homeostasis along with new and improved therapies to treat musculoskeletal conditions.
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Fröbel J, Landspersky T, Percin G, Schreck C, Rahmig S, Ori A, Nowak D, Essers M, Waskow C, Oostendorp RAJ. The Hematopoietic Bone Marrow Niche Ecosystem. Front Cell Dev Biol 2021; 9:705410. [PMID: 34368155 PMCID: PMC8339972 DOI: 10.3389/fcell.2021.705410] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/28/2021] [Indexed: 12/18/2022] Open
Abstract
The bone marrow (BM) microenvironment, also called the BM niche, is essential for the maintenance of fully functional blood cell formation (hematopoiesis) throughout life. Under physiologic conditions the niche protects hematopoietic stem cells (HSCs) from sustained or overstimulation. Acute or chronic stress deregulates hematopoiesis and some of these alterations occur indirectly via the niche. Effects on niche cells include skewing of its cellular composition, specific localization and molecular signals that differentially regulate the function of HSCs and their progeny. Importantly, while acute insults display only transient effects, repeated or chronic insults lead to sustained alterations of the niche, resulting in HSC deregulation. We here describe how changes in BM niche composition (ecosystem) and structure (remodeling) modulate activation of HSCs in situ. Current knowledge has revealed that upon chronic stimulation, BM remodeling is more extensive and otherwise quiescent HSCs may be lost due to diminished cellular maintenance processes, such as autophagy, ER stress response, and DNA repair. Features of aging in the BM ecology may be the consequence of intermittent stress responses, ultimately resulting in the degeneration of the supportive stem cell microenvironment. Both chronic stress and aging impair the functionality of HSCs and increase the overall susceptibility to development of diseases, including malignant transformation. To understand functional degeneration, an important prerequisite is to define distinguishing features of unperturbed niche homeostasis in different settings. A unique setting in this respect is xenotransplantation, in which human cells depend on niche factors produced by other species, some of which we will review. These insights should help to assess deviations from the steady state to actively protect and improve recovery of the niche ecosystem in situ to optimally sustain healthy hematopoiesis in experimental and clinical settings.
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Affiliation(s)
- Julia Fröbel
- Immunology of Aging, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany
| | - Theresa Landspersky
- School of Medicine, Department of Internal Medicine III, Technical University of Munich, Munich, Germany
| | - Gülce Percin
- Immunology of Aging, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany
| | - Christina Schreck
- School of Medicine, Department of Internal Medicine III, Technical University of Munich, Munich, Germany
| | - Susann Rahmig
- Immunology of Aging, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany
| | - Alessandro Ori
- Proteomics of Aging, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany
| | - Daniel Nowak
- Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Marieke Essers
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.,Division Inflammatory Stress in Stem Cells, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Claudia Waskow
- Immunology of Aging, Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany.,Institute of Biochemistry and Biophysics, Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany.,Department of Medicine III, Technical University Dresden, Dresden, Germany
| | - Robert A J Oostendorp
- School of Medicine, Department of Internal Medicine III, Technical University of Munich, Munich, Germany
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Association between miRNA Target Sites and Incidence of Primary Osteoarthritis in Women from Volga-Ural Region of Russia: A Case-Control Study. Diagnostics (Basel) 2021; 11:diagnostics11071222. [PMID: 34359306 PMCID: PMC8306068 DOI: 10.3390/diagnostics11071222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 11/30/2022] Open
Abstract
Over the past decades, numerous studies on the genetic markers of osteoarthritis (OA) have been conducted. MiRNA targets sites are a promising new area of research. In this study, we analyzed the polymorphic variants in 3′ UTR regions of COL1A1, COL11A1, ADAMTS5, MMP1, MMP13, SOX9, GDF5, FGF2, FGFR1, and FGFRL1 genes to examine the association between miRNA target site alteration and the incidence of OA in women from the Volga-Ural region of Russia using competitive allele-specific PCR. The T allele of the rs9659030 was associated with generalized OA (OR = 2.0), whereas the C allele of the rs229069 was associated with total OA (OR = 1.43). The T allele of the rs13317 was associated with the total OA (OR = 1.67). After Benjamini-Hochberg correction, only rs13317 remained statistically significant. According to ethnic heterogeneity, associations between the T allele (rs1061237) with OA in women of Russian descent (OR = 1.77), the G allele (rs6854081) in women of Tatar descent (OR = 4.78), the C allele (rs229069) and the T allele (rs73611720) in women of mixed descent and other ethnic groups (OR = 2.25 and OR = 3.02, respectively) were identified. All associations remained statistically significant after Benjamini-Hochberg correction. Together, this study identified miRNA target sites as a genetic marker for the development of OA in various ethnic groups.
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6
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Al-Khan AA, Al Balushi NR, Richardson SJ, Danks JA. Roles of Parathyroid Hormone-Related Protein (PTHrP) and Its Receptor (PTHR1) in Normal and Tumor Tissues: Focus on Their Roles in Osteosarcoma. Front Vet Sci 2021; 8:637614. [PMID: 33796580 PMCID: PMC8008073 DOI: 10.3389/fvets.2021.637614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/17/2021] [Indexed: 12/17/2022] Open
Abstract
Osteosarcoma (OS) is the most common primary bone tumor and originates from bone forming mesenchymal cells and primarily affects children and adolescents. The 5-year survival rate for OS is 60 to 65%, with little improvement in prognosis during the last four decades. Studies have demonstrated the evolving roles of parathyroid hormone-related protein (PTHrP) and its receptor (PTHR1) in bone formation, bone remodeling, regulation of calcium transport from blood to milk, regulation of maternal calcium transport to the fetus and reabsorption of calcium in kidneys. These two molecules also play critical roles in the development, progression and metastasis of several tumors such as breast cancer, lung carcinoma, chondrosarcoma, squamous cell carcinoma, melanoma and OS. The protein expression of both PTHrP and PTHR1 have been demonstrated in OS, and their functions and proposed signaling pathways have been investigated yet their roles in OS have not been fully elucidated. This review aims to discuss the latest research with PTHrP and PTHR1 in OS tumorigenesis and possible mechanistic pathways. This review is dedicated to Professor Michael Day who died in May 2020 and was a very generous collaborator.
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Affiliation(s)
- Awf A Al-Khan
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.,Department of Pathology, Sohar Hospital, Sohar, Oman
| | - Noora R Al Balushi
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
| | - Samantha J Richardson
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.,School of Science, RMIT University, Bundoora, VIC, Australia
| | - Janine A Danks
- School of Science, RMIT University, Bundoora, VIC, Australia.,The University of Melbourne, Department of Medicine, Austin Health, Heidelberg, VIC, Australia
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7
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Agas D, Amaroli A, Lacava G, Yanagawa T, Sabbieti MG. Loss of p62 impairs bone turnover and inhibits PTH-induced osteogenesis. J Cell Physiol 2020; 235:7516-7529. [PMID: 32100883 DOI: 10.1002/jcp.29654] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 02/12/2020] [Indexed: 12/17/2022]
Abstract
The p62 (also named sequestosome1/SQSTM1) is multidomain and multifunctional protein associated with several physiological and pathological conditions. A number of studies evidenced an involvement of p62 on the disruptive bone scenarios due to its participation in the inflammatory/osteoclastogenic pathways. However, so far, information regarding the function of p62 in the fine-tuned processes underpinning the bone physiology are not well-defined and are sometime discordant. We, previously, demonstrated that the intramuscular administration of a plasmid coding for p62 was able to contrast bone loss in a mouse model of osteopenia. Here, in vitro findings showed that the p62 overexpression in murine osteoblasts precursors enhanced their maturation while the p62 depletion by a specific siRNA, decreased osteoblasts differentiation. Consistently, the activity of osteoblasts from p62-/- mice was reduced compared with wild-type. Also, morphometric analyses of bone from p62 knockout mice revealed a pathological phenotype characterized by a lower turnover that could be explained by the poor Runx2 protein synthesis in absence of p62. Furthermore, we demonstrated that the parathyroid hormone (PTH) regulates p62 expression and that the osteogenic effects of this hormone were totally abrogated in osteoblasts from p62-deficient mice. Therefore, these findings, for the first time, highlight the important role of p62 both for the basal and for PTH-stimulated bone remodeling.
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Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Andrea Amaroli
- Department of Surgical and Diagnostic Sciences, Laser Therapy Center, University of Genoa, Genoa, Italy
| | - Giovanna Lacava
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Toru Yanagawa
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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8
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Lerner UH, Kindstedt E, Lundberg P. The critical interplay between bone resorbing and bone forming cells. J Clin Periodontol 2019; 46 Suppl 21:33-51. [DOI: 10.1111/jcpe.13051] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 11/05/2018] [Accepted: 12/01/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Ulf H. Lerner
- Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition; Institute of Medicine; Sahlgrenska Academy; University of Gothenburg; Gothenburg Sweden
- Department of Odontology; Division of Molecular Periodontology; Umeå University; Umeå Sweden
| | - Elin Kindstedt
- Department of Odontology; Division of Molecular Periodontology; Umeå University; Umeå Sweden
| | - Pernilla Lundberg
- Department of Odontology; Division of Molecular Periodontology; Umeå University; Umeå Sweden
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9
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Adhikary S, Choudhary D, Tripathi AK, Karvande A, Ahmad N, Kothari P, Trivedi R. FGF-2 targets sclerostin in bone and myostatin in skeletal muscle to mitigate the deleterious effects of glucocorticoid on musculoskeletal degradation. Life Sci 2019; 229:261-276. [PMID: 31082400 DOI: 10.1016/j.lfs.2019.05.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/03/2019] [Accepted: 05/09/2019] [Indexed: 10/26/2022]
Abstract
AIM Myokines are associated with regulation of bone and muscle mass. However, limited information is available regarding the impact of myokines on glucocorticoid (GC) mediated adverse effects on the musculoskeletal system. This study investigates the role of myokine fibroblast growth factor-2 (FGF-2) in regulating GC-induced deleterious effects on bone and skeletal muscle. METHODS Primary osteoblast cells and C2C12 myoblast cell line were treated with FGF-2 and then exposed to dexamethasone (GC). FGF-2 mediated attenuation of the inhibitory effect of GC on osteoblast and myoblast differentiation and muscle atrophy was assessed through quantitative PCR and western blot analysis. Further, FGF-2 was administered subcutaneously to dexamethasone treated mice to collect bone and skeletal muscle tissue for in vivo analysis of bone microarchitecture, mechanical strength, histomorphometry and for histological alterations in treated tissue samples. KEY FINDINGS FGF-2 abrogated the dexamethasone induced inhibitory effect on osteoblast differentiation by modulating BMP-2 pathway and inhibiting Wnt antagonist sclerostin. Further, dexamethasone induced atrophy in C2C12 cells was mitigated by FGF-2 as evident from down regulation of atrogenes expression. FGF-2 prevented GC-induced impairment of mineral density, biomechanical strength, trabecular bone volume, cortical thickness and bone formation rate in mice. Additionally, skeletal muscle tissue from GC treated mice displayed weak myostatin immunostaining and reduced expression of atrogenes following FGF-2 treatment. SIGNIFICANCE FGF-2 mitigated GC induced effects through inhibition of sclerostin and myostatin expression in bone and muscle respectively. Taken together, this study exhibited the role of exogenous FGF-2 in sustaining osteoblastogenesis and inhibiting muscle atrophy in presence of glucocorticoid.
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Affiliation(s)
- Sulekha Adhikary
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Dharmendra Choudhary
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Ashish Kumar Tripathi
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Anirudha Karvande
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Naseer Ahmad
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Priyanka Kothari
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Ritu Trivedi
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
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10
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Agas D, Laus F, Lacava G, Marchegiani A, Deng S, Magnoni F, Silva GG, Di Martino P, Sabbieti MG, Censi R. Thermosensitive hybrid hyaluronan/p(HPMAm-lac)-PEG hydrogels enhance cartilage regeneration in a mouse model of osteoarthritis. J Cell Physiol 2019; 234:20013-20027. [PMID: 30968404 DOI: 10.1002/jcp.28598] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/16/2019] [Accepted: 03/19/2019] [Indexed: 02/06/2023]
Abstract
Osteoarthritis (OA), due to cartilage degeneration, is one of the leading causes of disability worldwide. Currently, there are not efficacious therapies to reverse cartilage degeneration. In this study we evaluated the potential of hybrid hydrogels, composed of a biodegradable and thermosensitive triblock copolymer cross-linked via Michael addition to thiolated hyaluronic acid, in contrasting inflammatory processes underlying OA. Hydrogels composed of different w/w % concentrations of hyaluronan were investigated for their degradation behavior and capacity to release the polysaccharide in a sustained fashion. It was found that hyaluronic acid was controllably released during network degradation with a zero-order release kinetics, and the release rate depended on cross-link density and degradation kinetics of the hydrogels. When locally administered in vivo in an OA mouse model, the hydrogels demonstrated the ability to restore, to some extent, bone remineralization, proteoglycan production, levels of Sox-9 and Runx-2. Furthermore, the downregulation of proinflammatory mediators, such as TNF-α, NFkB, and RANKL and proinflammatory cytokines was observed. In summary, the investigated hydrogel technology represents an ideal candidate for the potential encapsulation and release of drugs relevant in the field of OA. In this context, the hydrogel matrix could act in synergy with the drug, in reversing phenomena of inflammation, cartilage disruption, and bone demineralization associated with OA.
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Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Macerata, Italy
| | - Fulvio Laus
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Macerata, Italy
| | - Giovanna Lacava
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Macerata, Italy
| | - Andrea Marchegiani
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Macerata, Italy
| | - Siyuan Deng
- School of Pharmacy, University of Camerino, Camerino, Macerata, Italy
| | - Federico Magnoni
- School of Pharmacy, University of Camerino, Camerino, Macerata, Italy
| | - Guilherme Gusmão Silva
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Macerata, Italy.,Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Piera Di Martino
- School of Pharmacy, University of Camerino, Camerino, Macerata, Italy
| | - Maria Giovanna Sabbieti
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Macerata, Italy
| | - Roberta Censi
- School of Pharmacy, University of Camerino, Camerino, Macerata, Italy
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11
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Abstract
Fibroblast growth factors (FGFs) and their receptors (FGFRs) are expressed throughout all stages of skeletal development. In the limb bud and in cranial mesenchyme, FGF signaling is important for formation of mesenchymal condensations that give rise to bone. Once skeletal elements are initiated and patterned, FGFs regulate both endochondral and intramembranous ossification programs. In this chapter, we review functions of the FGF signaling pathway during these critical stages of skeletogenesis, and explore skeletal malformations in humans that are caused by mutations in FGF signaling molecules.
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Affiliation(s)
- David M Ornitz
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States.
| | - Pierre J Marie
- UMR-1132 Inserm (Institut national de la Santé et de la Recherche Médicale) and University Paris Diderot, Sorbonne Paris Cité, Hôpital Lariboisière, Paris, France
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12
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Cheng VKF, Au PCM, Tan KC, Cheung CL. MicroRNA and Human Bone Health. JBMR Plus 2018; 3:2-13. [PMID: 30680358 PMCID: PMC6339549 DOI: 10.1002/jbm4.10115] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/05/2018] [Accepted: 10/09/2018] [Indexed: 12/19/2022] Open
Abstract
The small non‐coding microRNAs (miRNAs) are post‐transcription regulators that modulate diverse cellular process in bone cells. Because optimal miRNA targeting is essential for their function, single‐nucleotide polymorphisms (SNPs) within or proximal to the loci of miRNA (miR‐SNPs) or mRNA (PolymiRTS) could potentially disrupt the miRNA‐mRNA interaction, leading to changes in bone metabolism and osteoporosis. Recent human studies of skeletal traits using miRNA profiling, genomewide association studies, and functional studies started to decipher the complex miRNA regulatory network. These studies have indicated that miRNAs may be a promising bone marker. This review focuses on human miRNA studies on bone traits and discusses how genetic variants affect bone metabolic pathways. Major ex vivo investigations using human samples supported with animal and in vitro models have shed light on the mechanistic role of miRNAs. Furthermore, studying the miRNAs’ signatures in secondary osteoporosis and osteoporotic medications such as teriparatide (TPTD) and denosumab (DMab) have provided valuable insight into clinical management of the disease. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research
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Affiliation(s)
- Vincent Ka-Fai Cheng
- Department of Pharmacology and Pharmacy The University of Hong Kong Pokfulam Hong Kong
| | - Philip Chun-Ming Au
- Department of Pharmacology and Pharmacy The University of Hong Kong Pokfulam Hong Kong
| | - Kathryn Cb Tan
- Department of Medicine The University of Hong Kong Pokfulam Hong Kong
| | - Ching-Lung Cheung
- Department of Pharmacology and Pharmacy The University of Hong Kong Pokfulam Hong Kong.,Centre for Genomic Sciences Li Ka Shing Faculty of Medicine The University of Hong Kong Pokfulam Hong Kong
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13
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Xiao L, Fei Y, Hurley MM. FGF2 crosstalk with Wnt signaling in mediating the anabolic action of PTH on bone formation. Bone Rep 2018; 9:136-144. [PMID: 30258857 PMCID: PMC6152810 DOI: 10.1016/j.bonr.2018.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/30/2018] [Accepted: 09/20/2018] [Indexed: 12/20/2022] Open
Abstract
The mechanisms of the anabolic effect of parathyroid hormone (PTH) in bone are not fully defined. The bone anabolic effects of PTH require fibroblast growth factor 2 (FGF2) as well as Wnt signaling and FGF2 modulates Wnt signaling in osteoblasts. In vivo PTH administration differentially modulated Wnt signaling in bones of wild type (WT) and in mice that Fgf2 was knocked out (Fgf2KO). PTH increased Wnt10b mRNA and protein in WT but not in KO mice. Wnt antagonist SOST mRNA and protein was significantly higher in KO group. However, PTH decreased Sost mRNA significantly in WT as well as in Fgf2KO mice, but to a lesser extent in Fgf2KO. Dickhopf 2 (DKK2) is critical for osteoblast mineralization. PTH increased Dkk2 mRNA in WT mice but the response was impaired in Fgf2KO mice. PTH significantly increased Lrp5 mRNA and phosphorylation of Lrp6 in WT but the increase was markedly attenuated in Fgf2KO mice. PTH increased β-catenin expression and Wnt/β-catenin transcriptional activity significantly in WT but not in Fgf2KO mice. These data suggest that the impaired bone anabolic response to PTH in Fgf2KO mice is partially mediated by attenuated Wnt signaling.
In vivo PTH administration differentially modulated Wnt signaling in bones of WT and Fgf2KO mice. PTH treatment increased WNT10b and DKK2 expression in WT mice but the increase was blunted in Fgf2KO mice PTH increased Lrp5 mRNA and phosphorylation of Lrp6 in WT but the increase was markedly attenuated in Fgf2KO mice. PTH treatment increased β-catenin protein level and Wnt/β-catenin transcriptional activity in WT but not in Fgf2KO mice The impaired bone anabolic response to PTH in Fgf2KO mice is partially mediated by attenuated Wnt signaling.
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Affiliation(s)
| | | | - Marja M. Hurley
- Corresponding author at: Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, USA.
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Agas D, Lacava G, Sabbieti MG. Bone and bone marrow disruption by endocrine‐active substances. J Cell Physiol 2018; 234:192-213. [DOI: 10.1002/jcp.26837] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 05/09/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Veterinary Medicine University of Camerino Camerino Italy
| | - Giovanna Lacava
- School of Biosciences and Veterinary Medicine University of Camerino Camerino Italy
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15
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IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition. Bone Res 2018; 6:5. [PMID: 29507819 PMCID: PMC5827661 DOI: 10.1038/s41413-017-0002-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 04/25/2017] [Accepted: 05/02/2017] [Indexed: 02/05/2023] Open
Abstract
Parathyroid hormone (PTH) regulates bone remodeling by activating PTH type 1 receptor (PTH1R) in osteoblasts/osteocytes. Insulin-like growth factor type 1 (IGF-1) stimulates mesenchymal stem cell differentiation to osteoblasts. However, little is known about the signaling mechanisms that regulates the osteoblast-to-osteocyte transition. Here we report that PTH and IGF-I synergistically enhance osteoblast-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytoplasmic domain of PTH1R can be phosphorylated by insulin-like growth factor type I receptor (IGF1R) in vitro. Phosphorylated PTH1R localized to the barbed ends of actin filaments and increased actin polymerization during morphological change of osteoblasts into osteocytes. Disruption of the phosphorylation site reduced actin polymerization and dendrite length. Mouse models with conditional ablation of PTH1R in osteoblasts demonstrated a reduction in the number of osteoctyes and dendrites per osteocyte, with complete overlap of PTH1R with phosphorylated-PTH1R positioning in osteocyte dendrites in wild-type mice. Thus, our findings reveal a novel signaling mechanism that enhances osteoblast-to-osteocyte transition by direct phosphorylation of PTH1R by IGF1R. A key hormone and growth factor work together to help turn bone-forming cells into mature bone. Janet Crane and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, tested the effects of parathyroid hormone (PTH) and insulin like-growth factor type 1 (IGF-1) signaling on the differentiation of bone-forming osteoblasts by modulating the activity of their receptors in genetically engineered mice. They found a specific part of the PTH type 1 receptor has a phosphate group added to it by the IGF-1 receptor. This chemical tagging leads to changes in the cytoskeleton of osteoblasts that enhance the formation of mature bone cells known as osteocytes. Mice without this PTH receptor had reduced numbers of osteocytes in their bone. The findings reveal a novel signaling mechanism behind this cellular transition during bone building.
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16
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Mendes LF, Tam WL, Chai YC, Geris L, Luyten FP, Roberts SJ. Combinatorial Analysis of Growth Factors Reveals the Contribution of Bone Morphogenetic Proteins to Chondrogenic Differentiation of Human Periosteal Cells. Tissue Eng Part C Methods 2017; 22:473-86. [PMID: 27018617 DOI: 10.1089/ten.tec.2015.0436] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Successful application of cell-based strategies in cartilage and bone tissue engineering has been hampered by the lack of robust protocols to efficiently differentiate mesenchymal stem cells into the chondrogenic lineage. The development of chemically defined culture media supplemented with growth factors (GFs) has been proposed as a way to overcome this limitation. In this work, we applied a fractional design of experiment (DoE) strategy to screen the effect of multiple GFs (BMP2, BMP6, GDF5, TGF-β1, and FGF2) on chondrogenic differentiation of human periosteum-derived mesenchymal stem cells (hPDCs) in vitro. In a micromass culture (μMass) system, BMP2 had a positive effect on glycosaminoglycan deposition at day 7 (p < 0.001), which in combination with BMP6 synergistically enhanced cartilage-like tissue formation that displayed in vitro mineralization capacity at day 14 (p < 0.001). Gene expression of μMasses cultured for 7 days with a medium formulation supplemented with 100 ng/mL of BMP2 and BMP6 and a low concentration of GDF5, TGF-β1, and FGF2 showed increased expression of Sox9 (1.7-fold) and the matrix molecules aggrecan (7-fold increase) and COL2A1 (40-fold increase) compared to nonstimulated control μMasses. The DoE analysis indicated that in GF combinations, BMP2 was the strongest effector for chondrogenic differentiation of hPDCs. When transplanted ectopically in nude mice, the in vitro-differentiated μMasses showed maintenance of the cartilaginous phenotype after 4 weeks in vivo. This study indicates the power of using the DoE approach for the creation of new medium formulations for skeletal tissue engineering approaches.
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Affiliation(s)
- Luis Filipe Mendes
- 1 Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center , Katholieke Universiteit Leuven, Leuven, Belgium .,2 Prometheus, Division of Skeletal Tissue Engineering, Katholieke Universiteit Leuven , Leuven, Belgium
| | - Wai Long Tam
- 1 Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center , Katholieke Universiteit Leuven, Leuven, Belgium .,2 Prometheus, Division of Skeletal Tissue Engineering, Katholieke Universiteit Leuven , Leuven, Belgium
| | - Yoke Chin Chai
- 1 Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center , Katholieke Universiteit Leuven, Leuven, Belgium .,2 Prometheus, Division of Skeletal Tissue Engineering, Katholieke Universiteit Leuven , Leuven, Belgium
| | - Liesbet Geris
- 2 Prometheus, Division of Skeletal Tissue Engineering, Katholieke Universiteit Leuven , Leuven, Belgium .,3 Biomechanics Research Unit, University of Liege , Liege, Belgium .,4 Department of Mechanical Engineering, Biomechanics Section, Katholieke Universiteit Leuven, Heverlee, Belgium
| | - Frank P Luyten
- 1 Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center , Katholieke Universiteit Leuven, Leuven, Belgium .,2 Prometheus, Division of Skeletal Tissue Engineering, Katholieke Universiteit Leuven , Leuven, Belgium
| | - Scott J Roberts
- 1 Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center , Katholieke Universiteit Leuven, Leuven, Belgium .,2 Prometheus, Division of Skeletal Tissue Engineering, Katholieke Universiteit Leuven , Leuven, Belgium .,5 Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery and Interventional Science, University College London , The Royal National Orthopaedic Hospital, London, United Kingdom
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Siddiqui JA, Partridge NC. Physiological Bone Remodeling: Systemic Regulation and Growth Factor Involvement. Physiology (Bethesda) 2017; 31:233-45. [PMID: 27053737 DOI: 10.1152/physiol.00061.2014] [Citation(s) in RCA: 265] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Bone remodeling is essential for adult bone homeostasis. It comprises two phases: bone formation and resorption. The balance between the two phases is crucial for sustaining bone mass and systemic mineral homeostasis. This review highlights recent work on physiological bone remodeling and discusses our knowledge of how systemic and growth factors regulate this process.
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Affiliation(s)
- Jawed A Siddiqui
- Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York
| | - Nicola C Partridge
- Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York
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18
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Nikitovic D, Kavasi RM, Berdiaki A, Papachristou DJ, Tsiaoussis J, Spandidos DA, Tsatsakis AM, Tzanakakis GN. Parathyroid hormone/parathyroid hormone-related peptide regulate osteosarcoma cell functions: Focus on the extracellular matrix (Review). Oncol Rep 2016; 36:1787-92. [PMID: 27499459 PMCID: PMC5022866 DOI: 10.3892/or.2016.4986] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 07/15/2016] [Indexed: 12/25/2022] Open
Abstract
Osteosarcoma (OS) is a primary bone tumor of mesenchymal origin mostly affecting children and adolescents. The OS extracellular matrix (ECM) is extensively altered as compared to physiological bone tissue. Indeed, the main characteristic of the most common osteoblastic subtype of OS is non-mineralized osteoid production. Parathyroid hormone (PTH) is a polypeptide hormone secreted by the chief cells of the parathyroid glands. The PTH-related peptide (PTHrP) may be comprised of 139, 141 or 173 amino acids and exhibits considerate N-terminal amino acid sequence homology with PTH. The function of PTH/PTHrP is executed through the activation of the PTH receptor 1 (PTHR1) and respective downstream intracellular pathways which regulate skeletal development, bone turnover and mineral ion homeostasis. Both PTHR1 and its PTH/PTHrP ligands have been shown to be expressed in OS and to affect the functions of these tumor cells. This review aims to highlight the less well known aspects of PTH/PTHrP functions in the progression of OS by focusing on ECM-dependent signaling.
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Affiliation(s)
- Dragana Nikitovic
- Department of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, Heraklion 71003, Greece
| | - Rafaela-Maria Kavasi
- Department of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, Heraklion 71003, Greece
| | - Aikaterini Berdiaki
- Department of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, Heraklion 71003, Greece
| | - Dionysios J Papachristou
- Department of Anatomy‑Histology‑Embryology, Unit of Bone and Soft Tissue Studies, School of Medicine, University of Patras, Patras 26504, Greece
| | - John Tsiaoussis
- Department of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, Heraklion 71003, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion 71003, Greece
| | - Aristides M Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, Heraklion 71003, Greece
| | - George N Tzanakakis
- Department of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, Heraklion 71003, Greece
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19
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Xie Y, Yi L, Weng T, Huang J, Luo F, Jiang W, Xian CJ, Du X, Chen L. Fibroblast Growth Factor Receptor 3 Deficiency Does Not Impair the Osteoanabolic Action of Parathyroid Hormone on Mice. Int J Biol Sci 2016; 12:990-9. [PMID: 27489502 PMCID: PMC4971737 DOI: 10.7150/ijbs.14077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 04/18/2016] [Indexed: 01/14/2023] Open
Abstract
Summary: PTH stimulates bone formation in Fgfr3 knockout mice through promotion of proliferation and differentiation in osteoblasts. Introduction: Previous studies showed that endogenous fibroblast growth factor 2 (FGF-2) is required for parathyroid hormone (PTH)-stimulated bone anabolic effects, however, the exact mechanisms by which PTH stimulate bone formation and the function of FGF receptors in mediating these actions are not fully defined. FGF receptor 3 (FGFR3) has been characterized as an important regulator of bone metabolism and is confirmed to cross-talk with PTH/PTHrP signal in cartilage and bone development. Methods: Fgfr3 knockout and wild-type mice at 2-month-old and 4-month-old were intraperitoneally injected with PTH intermittently for 4 weeks and then the skeletal responses to PTH were assessed by dual energy X-ray absorptiometry (DEXA), micro-computed tomography (μCT) and bone histomorphometry. Results: Intermittent PTH treatment improved bone mineral density (BMD) and femoral mechanical properties in both Fgfr3-/- and wild-type mice. Histomorphometric analysis showed that bone formation and bone resorption were increased in both genotypes following PTH treatment. PTH treatment increased trabecular bone volume (BV/TV) in WT and Fgfr3-deficient mice. The anabolic response in Fgfr3-deficient and wild-type bone is characterized by an increase of both bone formation and resorption-related genes following PTH treatment. In addition, we found that Fgfr3 null osteoblasts (compared to wild-type controls) maintained normal abilities to response to PTH-stimulated increase of proliferation, differentiation, expression of osteoblastic marker genes (Cbfa1, Osteopontin and Osteocalcin), and phosphorylation of Erk1/2. Conclusions: Bone anabolic effects of PTH were not impaired by the absence of FGFR3, suggesting that the FGFR3 signaling may not be required for osteoanabolic effects of PTH activities.
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Affiliation(s)
- Yangli Xie
- 1. Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Lingxian Yi
- 1. Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China;; 3. Intensive Care Unit, The 306th hospital of PLA, Beijing 100101, China
| | - Tujun Weng
- 1. Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Junlan Huang
- 1. Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Fengtao Luo
- 1. Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Wanling Jiang
- 1. Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Cory J Xian
- 2. Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia
| | - Xiaolan Du
- 1. Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Lin Chen
- 1. Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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20
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Hurley MM, Gronowicz G, Zhu L, Kuhn LT, Rodner C, Xiao L. Age-Related Changes in FGF-2, Fibroblast Growth Factor Receptors and β-Catenin Expression in Human Mesenchyme-Derived Progenitor Cells. J Cell Biochem 2015; 117:721-9. [PMID: 26332075 DOI: 10.1002/jcb.25357] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 08/31/2015] [Indexed: 12/14/2022]
Abstract
FGF-2 stimulates preosteoblast replication, and knockout of the FGF-2 gene in mice resulted in osteopenia with age, associated with decreased Wnt-β-Catenin signaling. In addition, targeted expression of FGF-2 in osteoblast progenitors increased bone mass in mice via Wnt-β-Catenin signaling. We posited that diminution of the intrinsic proliferative capacity of human mesenchyme-derived progenitor cells (HMDPCs) with age is due in part to reduction in FGF-2. To test this hypothesis HMDPCs from young (27-38), middle aged (47-56), and old (65-76) female human subjects were isolated from bone discarded after orthopedic procedures. HMDPCs cultures were mostly homogeneous with greater than 90% mesenchymal progenitor cells, determined by fluorescence-activated cell sorting. There was a progressive decrease in FGF-2 and FGFR1 mRNA and protein in HMDPCs with age. Since FGF-2 activates β-catenin, which can enhance bone formation, we also assessed its age-related expression in HMDPCs. An age-related decrease in total-β-Catenin mRNA and protein expression was observed. However there were increased levels of p-β-Catenin and decreased levels of activated-β-Catenin in old HMDSCs. FGF-2 treatment increased FGFR1 and β-Catenin protein, reduced the level of p-β-Catenin and increased activated-β-Catenin in aged HMDPCs. In conclusion, reduction in FGF-2 expression could contribute to age-related impaired function of HMDPCs via modulation of Wnt-β-catenin signaling.
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Affiliation(s)
| | | | - Li Zhu
- Department of Reconstructive Sciences, UCONN Health, Farmington, CT
| | - Liisa T Kuhn
- Department of Reconstructive Sciences, UCONN Health, Farmington, CT
| | - Craig Rodner
- Department of Orthopedics, UCONN Health, Farmington, CT
| | - Liping Xiao
- Department of Medicine, UCONN Health, Farmington, CT
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Abstract
Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.
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Affiliation(s)
- David M Ornitz
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - Pierre J Marie
- UMR-1132, Institut National de la Santé et de la Recherche Médicale, Hopital Lariboisiere, 75475 Paris Cedex 10, France; Université Paris Diderot, Sorbonne Paris Cité, 75475 Paris Cedex 10, France
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22
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Agas D, Marchetti L, Douni E, Sabbieti MG. The unbearable lightness of bone marrow homeostasis. Cytokine Growth Factor Rev 2015; 26:347-59. [DOI: 10.1016/j.cytogfr.2014.12.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 11/22/2014] [Accepted: 12/17/2014] [Indexed: 01/10/2023]
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23
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Li P, Zhou Z, Shi C, Hou J. Downregulation of basic fibroblast growth factor is associated with femoral head necrosis in broilers. Poult Sci 2015; 94:1052-9. [DOI: 10.3382/ps/pev071] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2015] [Indexed: 12/14/2022] Open
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Xie Y, Zhou S, Chen H, Du X, Chen L. Recent research on the growth plate: Advances in fibroblast growth factor signaling in growth plate development and disorders. J Mol Endocrinol 2014; 53:T11-34. [PMID: 25114206 DOI: 10.1530/jme-14-0012] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Skeletons are formed through two distinct developmental actions, intramembranous ossification and endochondral ossification. During embryonic development, most bone is formed by endochondral ossification. The growth plate is the developmental center for endochondral ossification. Multiple signaling pathways participate in the regulation of endochondral ossification. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling has been found to play a vital role in the development and maintenance of growth plates. Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Clarifying the molecular mechanisms of FGFs/FGFRs signaling in skeletal development and genetic skeletal diseases will have implications for the development of therapies for FGF-signaling-related skeletal dysplasias and growth plate injuries. In this review, we summarize the recent advances in elucidating the role of FGFs/FGFRs signaling in growth plate development, genetic skeletal disorders, and the promising therapies for those genetic skeletal diseases resulting from FGFs/FGFRs dysfunction. Finally, we also examine the potential important research in this field in the future.
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Affiliation(s)
- Yangli Xie
- Department of Rehabilitation MedicineCenter of Bone Metabolism and Repair, Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Siru Zhou
- Department of Rehabilitation MedicineCenter of Bone Metabolism and Repair, Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Hangang Chen
- Department of Rehabilitation MedicineCenter of Bone Metabolism and Repair, Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Xiaolan Du
- Department of Rehabilitation MedicineCenter of Bone Metabolism and Repair, Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Lin Chen
- Department of Rehabilitation MedicineCenter of Bone Metabolism and Repair, Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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25
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Su N, Jin M, Chen L. Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res 2014; 2:14003. [PMID: 26273516 PMCID: PMC4472122 DOI: 10.1038/boneres.2014.3] [Citation(s) in RCA: 207] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Revised: 11/29/2013] [Accepted: 12/03/2013] [Indexed: 01/06/2023] Open
Abstract
Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-in/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis.
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Affiliation(s)
- Nan Su
- Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University , Chongqing, 400042, China
| | - Min Jin
- Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University , Chongqing, 400042, China
| | - Lin Chen
- Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University , Chongqing, 400042, China
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26
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Oh YI, Kim JH, Kang CW. Protective effect of short-term treatment with parathyroid hormone 1-34 on oxidative stress is involved in insulin-like growth factor-I and nuclear factor erythroid 2-related factor 2 in rat bone marrow derived mesenchymal stem cells. ACTA ACUST UNITED AC 2014; 189:1-10. [PMID: 24412273 DOI: 10.1016/j.regpep.2013.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 12/24/2013] [Accepted: 12/31/2013] [Indexed: 11/30/2022]
Abstract
Bone marrow-derived mesenchymal stem cell (MSC)-mediated regeneration is a promising treatment for degenerative disease and traumatic injuries. MSCs can be isolated from rats using magnetic-activated cell sorting with CD105 antibody. We investigated the relationships between the expression of endogenous insulin-like growth factor-I (IGF-I) and nuclear factor erythroid 2-related factor 2 (Nrf-2) during short-term treatment with parathyroid hormone (PTH) 1-34-induced protective response in MSCs. PTH 1-34 (10(-9)M) decreased reactive oxygen species (ROS) generation but increased cell viability and endogenous IGF-I (p<0.01). Suppression of IGF-I and Nrf-2 using specific small interfering RNA (siRNA) blocked the effects of PTH 1-34. Furthermore, increasing cell viability of PTH against hydrogen peroxide (H2O2) was suppressed by treatment with siRNA to IGF-I and Nr-2 (p<0.05). Exogenous IGF-I (10(-9)M) also increased endogenous IGF-I, cell viability, and Nrf-2 expression. These incremental increases were lessened by Nrf-2 siRNA (p<0.05). Exogenous IGF-I also inhibited the increase of H2O2-induced ROS generation, and the decrease of PTH 1-34-induced ROS generation in the presence of IGF-I and Nrf-2 siRNA. The increase of PTH 1-34-induced Nrf-2 expression was more significant in the nucleus than in the cytosol (p<0.05). PTH 1-34 also inhibited H2O2-induced inducible nitric oxide synthase expression, but increased the expression of heme oxygenase 1/2. The results implicate PTH 1-34, Nrf-2, and IGF-I signaling pathways in the response to oxidative stress. These factors could influence IGF-I regulation of metabolic fate and survival in MSCs.
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Affiliation(s)
- Young-Il Oh
- Department of Veterinary Physiology, College of Veterinary Medicine/Bio-Safety Research Institute, Chonbuk National University, South Korea
| | - Jong-Hoon Kim
- Department of Veterinary Physiology, College of Veterinary Medicine/Bio-Safety Research Institute, Chonbuk National University, South Korea
| | - Chang-Won Kang
- Department of Veterinary Physiology, College of Veterinary Medicine/Bio-Safety Research Institute, Chonbuk National University, South Korea.
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Agas D, Marchetti L, Capitani M, Sabbieti MG. The dual face of parathyroid hormone and prostaglandins in the osteoimmune system. Am J Physiol Endocrinol Metab 2013; 305:E1185-94. [PMID: 24045870 DOI: 10.1152/ajpendo.00290.2013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The microenvironment of bone marrow, an extraordinarily heterogeneous and dynamic system, is populated by bone and immune cells, and its functional dimension has been at the forefront of recent studies in the field of osteoimmunology. The interaction of both marrow niches supports self-renewal, differentiation, and homing of the hematopoietic stem cells and provides the essential regulatory molecules for osteoblast and osteoclast homeostasis. Impaired signaling within the niches results in a pathological tableau and enhances disease, including osteoporosis and arthritis, or the rejection of hematopoietic stem cell transplants. Discovering the anabolic players that control these mechanisms has become warranted. In this review, we focus on parathyroid hormone (PTH) and prostaglandins (PGs), potent molecular mediators, both of which carry out a multitude of functions, particularly in bone lining cells and T cells. These two regulators proved to be promising therapeutic agents when strictly clinical protocols on dose treatments were applied.
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Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Biotechnology, University of Camerino, Italy
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Agas D, Sabbieti MG, Marchetti L, Xiao L, Hurley MM. FGF-2 enhances Runx-2/Smads nuclear localization in BMP-2 canonical signaling in osteoblasts. J Cell Physiol 2013; 228:2149-58. [PMID: 23559326 DOI: 10.1002/jcp.24382] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Accepted: 03/28/2013] [Indexed: 01/30/2023]
Abstract
Bone morphogenetic protein 2 (BMP-2) is one of the most potent regulators of osteoblast differentiation and bone formation. R-Smads (Smads 1/5/8) are the major transducers for BMPs receptors and, once activated, they are translocated in the nucleus regulating transcription target genes by interacting with various transcription factors. Runx-2 proteins have been shown to interact through their C-terminal segment with Smads and this interaction is required for in vivo osteogenesis. In particular, recruitment of Smads to intranuclear sites is Runx-2 dependent, and Runx-2 factor may accommodate the dynamic targeting of signal transducer to active transcription sites. Previously, we have shown, by in vitro and in vivo experiments, that BMP-2 up-regulated FGF-2 which is important for the maximal responses of BMP-2 in bone. In this study, we found that endogenous FGF2 is necessary for BMP-2 induced nuclear accumulation and co-localization of Runx-2 and phospho-Smads1/5/8, while Runx/Smads nuclear accumulation and co-localization was reduced in Fgf2-/- osteoblasts. Based on these novel data, we conclude that the impaired nuclear accumulation of Runx-2 in Fgf2-/- osteoblasts reduces R-Smads sub-nuclear targeting with a consequent decreased expression of differentiating markers and impaired bone formation in Fgf2 null mice.
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Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Biotechnology, University of Camerino, Camerino, Macerata, Italy
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29
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Fibroblast growth factor signaling promotes physiological bone remodeling and stem cell self-renewal. Curr Opin Hematol 2013; 20:237-44. [PMID: 23567340 DOI: 10.1097/moh.0b013e3283606162] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Fibroblast growth factor (FGF) signaling activates many bone marrow cell types, including various stem cells, osteoblasts, and osteoclasts. However, the role of FGF signaling in regulation of normal and leukemic stem cells is poorly understood. This review highlights the physiological roles of FGF signaling in regulating bone marrow mesenchymal and hematopoietic stem and progenitor cells (MSPCs and HSPCs) and their dynamic microenvironment. In addition, this review summarizes the recent studies which provide an overview of FGF-activated mechanisms regulating physiological stem cell maintenance, self-renewal, and motility. RECENT FINDINGS Current results indicate that partial deficiencies in FGF signaling lead to mild defects in hematopoiesis and bone remodeling. However, FGF signaling was shown to be crucial for stem cell self-renewal and for proper hematopoietic poststress recovery. FGF signaling activation was shown to be important also for rapid AMD3100 or post 5-fluorouracil-induced HSPC mobilization. In vivo, FGF-2 administration successfully expanded both MSPCs and HSPCs. FGF-induced expansion was characterized by enhanced HSPC cycling without further exhaustion of the stem cell pool. In addition, FGF signaling expands and remodels the supportive MSPC niche cells. Finally, FGF signaling is constitutively activated in many leukemias, suggesting that malignant HSPCs exploit this pathway for their constant expansion and for remodeling a malignant-supportive microenvironment. SUMMARY The summarized studies, concerning regulation of stem cells and their microenvironment, suggest that FGF signaling manipulation can serve to improve current clinical stem cell mobilization and transplantation protocols. In addition, it may help to develop therapies specifically targeting leukemic stem cells and their supportive microenvironment.
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Sabbieti MG, Agas D, Marchetti L, Coffin JD, Xiao L, Hurley MM. BMP-2 differentially modulates FGF-2 isoform effects in osteoblasts from newborn transgenic mice. Endocrinology 2013; 154:2723-33. [PMID: 23715864 PMCID: PMC3713219 DOI: 10.1210/en.2013-1025] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
We previously generated separate lines of transgenic mice that specifically overexpress either the Fibroblast growth factor (FGF)-2 low-molecular-mass isoform (Tg(LMW)) or the high-mass isoforms (Tg(HMW)) in the osteoblast lineage. Vector/control (Tg(Vector)) mice were also made. Here we report the use of isolated calvarial osteoblasts (COBs) from those mice to investigate whether the FGF-2 protein isoforms differentially modulate bone formation in vitro. Our hypothesis states that FGF-2 isoforms specifically modulate bone morphogenetic protein 2 (BMP-2) function and subsequently bone differentiation genes and their related signaling pathways. We found a significant increase in alkaline phosphatase-positive colonies in Tg(LMW) COBs compared with Tg(Vector) controls. BMP-2 treatment significantly increased mineralized colonies in Tg(Vector) and Tg(LMW) COBs. BMP-2 caused a further significant increase in mineralized colonies in Tg(LMW) COBs compared with Tg(Vector) COBs but did not increase alkaline phosphatase-positive colonies in Tg(HMW) COBs. Time-course studies showed that BMP-2 caused a sustained increase in phosphorylated mothers against decapentaplegic-1/5/8 (Smad/1/5/8), runt-related transcription factor-2 (Runx-2), and osterix protein in Tg(LMW) COBs. BMP-2 caused a sustained increase in phospho-p38 MAPK in Tg(Vector) but only a transient increase in Tg(LMW) and Tg(HMW) COBs. BMP-2 caused a transient increase in phospho-p44/42 MAPK in Tg(Vector) COBs and no increase in Tg(LMW) COBs, but a sustained increase was found in Tg(HMW) COBs. Basal expression of FGF receptor 1 protein was significantly increased in Tg(LMW) COBs relative to Tg(Vector) COBs, and although BMP-2 caused a transient increase in FGF receptor 1 expression in Tg(Vector) COBs and Tg(HMW) COBs, there was no further increase Tg(LMW) COBs. Interestingly, although basal expression of FGF receptor 2 was similar in COBs from all genotypes, BMP-2 treatment caused a sustained increase in Tg(LMW) COBs but decreased FGF receptor 2 in Tg(Vector) COBs and Tg(HMW) COBs.
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MESH Headings
- Alkaline Phosphatase/metabolism
- Animals
- Animals, Newborn
- Blotting, Western
- Bone Morphogenetic Protein 2/pharmacology
- Cells, Cultured
- Core Binding Factor Alpha 1 Subunit/metabolism
- Female
- Fibroblast Growth Factor 2/genetics
- Fibroblast Growth Factor 2/metabolism
- Humans
- Male
- Mice
- Mice, Transgenic
- Mitogen-Activated Protein Kinases/metabolism
- Osteoblasts/cytology
- Osteoblasts/drug effects
- Osteoblasts/metabolism
- Phosphorylation/drug effects
- Protein Isoforms/genetics
- Protein Isoforms/metabolism
- RNA Interference
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptor, Fibroblast Growth Factor, Type 1/metabolism
- Receptor, Fibroblast Growth Factor, Type 2/genetics
- Receptor, Fibroblast Growth Factor, Type 2/metabolism
- Skull/cytology
- Smad Proteins/metabolism
- Sp7 Transcription Factor
- Transcription Factors/metabolism
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31
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Esbrit P, Alcaraz MJ. Current perspectives on parathyroid hormone (PTH) and PTH-related protein (PTHrP) as bone anabolic therapies. Biochem Pharmacol 2013; 85:1417-23. [PMID: 23500550 DOI: 10.1016/j.bcp.2013.03.002] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 03/01/2013] [Accepted: 03/01/2013] [Indexed: 12/19/2022]
Abstract
Osteoporosis is characterized by low bone mineral density and/or poor bone microarchitecture leading to an increased risk of fractures. The skeletal alterations in osteoporosis are a consequence of a relative deficit of bone formation compared to bone resorption. Osteoporosis therapies have mostly relied on antiresorptive drugs. An alternative therapeutic approach for osteoporosis is currently available, based on the intermittent administration of parathyroid hormone (PTH). Bone anabolism caused by PTH therapy is mainly accounted for by the ability of PTH to increase osteoblastogenesis and osteoblast survival. PTH and PTH-related protein (PTHrP)-an abundant local factor in bone- interact with the common PTH type 1 receptor with similar affinities in osteoblasts. Studies mainly in osteoporosis rodent models and limited data in postmenopausal women suggest that N-terminal PTHrP peptides might be considered a promising bone anabolic therapy. In addition, putative osteogenic actions of PTHrP might be ascribed not only to its N-terminal domain but also to its PTH-unrelated C-terminal region. In this review, we discuss the underlying cellular and molecular mechanisms of the anabolic actions of PTH and the similar potential of PTH-related protein (PTHrP) to increase bone mass and improve bone regeneration.
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Affiliation(s)
- Pedro Esbrit
- Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria-IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain.
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32
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Kopic S, Geibel JP. Gastric acid, calcium absorption, and their impact on bone health. Physiol Rev 2013; 93:189-268. [PMID: 23303909 DOI: 10.1152/physrev.00015.2012] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Calcium balance is essential for a multitude of physiological processes, ranging from cell signaling to maintenance of bone health. Adequate intestinal absorption of calcium is a major factor for maintaining systemic calcium homeostasis. Recent observations indicate that a reduction of gastric acidity may impair effective calcium uptake through the intestine. This article reviews the physiology of gastric acid secretion, intestinal calcium absorption, and their respective neuroendocrine regulation and explores the physiological basis of a potential link between these individual systems.
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Affiliation(s)
- Sascha Kopic
- Department of Surgery and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA
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33
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Abstract
Bone microenvironment is a complex dynamic equilibrium between osteoclasts and osteoblasts and is modulated by a wide variety of hormones and osteocyte mediators secreted in response to physiological and pathological conditions. The rate of remodeling involves tight coupling and regulation of both cells population and is regulated by a wide variety of hormones and mediators such as parathyroid hormone, prostaglandins, thyroid hormone, sex steroids, etc. It is also well documented that bone formation is easily influenced by the exposure of osteoblasts and osteoclasts to chemical compounds. Currently, humans and wildlife animals are exposed to various environmental xenoestrogens typically at low doses. These compounds, known as endocrine disruptor chemicals (EDCs), can alter the systemic hormonal regulation of the bone remodeling process and the skeletal formation. This review highlights the effects of the EDCs on mammalian bone turnover and development providing a macro and molecular view of their action.
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Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Biotechnology, University of Camerino, Via Gentile III da Varano, 62032 Camerino, MC, Italy.
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34
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Fei Y, Hurley MM. Role of fibroblast growth factor 2 and Wnt signaling in anabolic effects of parathyroid hormone on bone formation. J Cell Physiol 2012; 227:3539-45. [PMID: 22378151 DOI: 10.1002/jcp.24075] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Osteoporosis poses enormous health and economic burden worldwide. One of the very few anabolic agents for osteoporosis is parathyroid hormone (PTH). Although great progress has been made since the FDA approved PTH in 2002, the detailed mechanisms of the bone anabolic effects of intermittent PTH treatment is still not well understood. PTH bone anabolic effect is regulated by extracellular factors. Maximal bone anabolic effect of PTH requires fibroblast growth factor 2 (FGF2) signaling, which might be mediated by transcription factor activating transcription factor 4 (ATF4). Maximal bone anabolic effect of PTH also requires Wnt signaling. Particularly, Wnt antagonists such as sclerostin, dickkopf 1 (DKK1) and secreted frizzled related protein 1 (sFRP1) are promising targets to increase bone formation. Interestingly, FGF2 signaling modulates Wnt/β-Catenin signaling pathway in bone. Therefore, multiple signaling pathways utilized by PTH are cross talking and working together to promote bone formation. Extensive studies on the mechanisms of action of PTH will help to identify new pathways that regulate bone formation, to improve available agents to stimulate bone formation, and to identify potential new anabolic agents for osteoporosis.
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Affiliation(s)
- Yurong Fei
- Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA
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35
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Serra Moreno J, Sabbieti MG, Agas D, Marchetti L, Panero S. Polysaccharides immobilized in polypyrrole matrices are able to induce osteogenic differentiation in mouse mesenchymal stem cells. J Tissue Eng Regen Med 2012; 8:989-99. [DOI: 10.1002/term.1601] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 06/07/2012] [Accepted: 07/23/2012] [Indexed: 12/14/2022]
Affiliation(s)
- Judith Serra Moreno
- Department of Chemistry; Sapienza University of Rome; Piazzale Aldo Moro 5 00185 Rome Italy
| | | | - Dimitrios Agas
- Department of Chemistry; Sapienza University of Rome; Piazzale Aldo Moro 5 00185 Rome Italy
- School of Biosciences and Biotechnology; University of Camerino; Camerino Italy
| | - Luigi Marchetti
- School of Biosciences and Biotechnology; University of Camerino; Camerino Italy
| | - Stefania Panero
- Department of Chemistry; Sapienza University of Rome; Piazzale Aldo Moro 5 00185 Rome Italy
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36
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Longo V, Brunetti O, D'Oronzo S, Dammacco F, Silvestris F. Therapeutic approaches to myeloma bone disease: an evolving story. Cancer Treat Rev 2012; 38:787-97. [PMID: 22494965 DOI: 10.1016/j.ctrv.2012.03.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 03/12/2012] [Accepted: 03/13/2012] [Indexed: 02/06/2023]
Abstract
Bone disease is a major morbidity factor in patients with multiple myeloma and significantly affects their overall survival. A complex interplay between malignant plasma cells and other marrow cells results in the generation of a microenvironment capable of enhancing both tumor growth and bone destruction. Bisphosphonates have consistently reduced the incidence of skeletal-related events in patients with multiple myeloma and other osteotropic tumors as well. However, their use is burdened with side-effects, including the risks of osteonecrosis of the jaw and kidney failure, suggesting that they should be discontinued after prolonged administration. New molecular targets of cell cross-talk in myeloma bone marrow are therefore under intensive investigation and new drugs are being explored in preclinical and clinical studies of myeloma bone disease. Compounds targeting osteoclast activation pathways, such as receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin, B-cell activating factor, mitogen-activated protein kinase and macrophage inflammatory protein-1α/chemokine receptor for macrophage inflammatory protein-1α axes, or soluble agents that improve osteoblast differentiation by modulating specific inhibitors such as Dickkopf-1 and transforming growth factor-β, as well as novel approaches of cytotherapy represent a new generation of promising drugs for the treatment of myeloma bone disease.
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Affiliation(s)
- Vito Longo
- DIMO, Department of Internal Medicine and Clinical Oncology, University of Bari 'Aldo Moro', Piazza Giulio Cesare, 11 - 70124 Bari, Italy.
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37
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Sabbieti MG, Agas D, Maggi F, Vittori S, Marchetti L. Molecular mediators involved in Ferulago campestris essential oil effects on osteoblast metabolism. J Cell Biochem 2012; 112:3742-54. [PMID: 21815199 DOI: 10.1002/jcb.23306] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
This study was performed to investigate the effects of the essential oil obtained from fruits of Ferulago campestris (FC) on primary calvarial mouse osteoblasts (COBs). The composition of the oil was dominated by monoterpene hydrocarbons (78.8-80.3%), with myrcene (33.4-39.7%), α-pinene (22.7-23.0%), and γ-terpinene (8.1-10.9%) as the major components. Owing to their lipophilic properties, these compounds easily cross cell membranes and affect bone cell function by stimulating or inhibiting specific molecular pathways. We demonstrated, for the first time, that FC oil increased osteoblast proliferation by MAP kinase activation; in addition, oils enhanced the protein kinase AKT, which is known to be critical for control of cell survival, also in presence of the MEK-1 inhibitor PD98059, and this effect was accompanied with a down-regulation of pro-apototic molecules such as Bax and caspases. Interestingly, FC oil significantly increased Runx2 (Runx2/Pebp2αA/AML3) and phospho-Smad1/5/8 protein level, the master regulators of osteoblast differentiation, and their nuclear localization. PD98059 pre-treatment further improved Runx2/phospho-Smads up-regulation. Thus, FC oils influence osteoblast metabolism probably using alternative signaling pathways depending also on the maturation stage of the cells. Taken together our data delineate a positive function of FC oil on osteoblast metabolism, suggesting its possible use as a dietetic integrator in the prevention or in the therapy of pathologies due to impaired bone remodeling.
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Affiliation(s)
- Maria Giovanna Sabbieti
- School of Biosciences and Biotechnology, University of Camerino, I-62032 Camerino (MC), Italy
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38
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Abstract
Fibroblast growth factors (FGFs) are important molecules that control bone formation. FGF act by activating FGF receptors (FGFRs) and downstream signaling pathways that control cells of the osteoblast lineage. Recent advances have been made in the identification of FGF/FGFR signaling pathways that control osteogenesis. Indeed, studies of mouse and human models provided novel insights into the signaling pathways that control bone formation. Genomic studies also highlighted the implication of molecular targets of FGF/FGFR signaling regulating osteoblastogenesis. Recent studies further revealed the important role of crosstalks between FGF/FGFR signaling and other signaling pathways in the regulation of osteogenesis. Finally, the importance of the mechanisms modulating FGFR degradation in the control of osteoblast differentiation has been recently revealed. This short review summarizes the recently described mechanisms underlying FGF/FGFR signaling that are involved in the control of osteoblastogenesis. This knowledge may have potential therapeutic implications in skeletal disorders characterized by abnormal bone formation.
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Affiliation(s)
- Pierre J Marie
- Laboratory of Osteoblast Biology and Pathology, INSERM UMR-606 and University Paris Diderot, Paris F-75475, France.
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39
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Marie PJ. Fibroblast growth factor signaling controlling bone formation: An update. Gene 2012; 498:1-4. [DOI: 10.1016/j.gene.2012.01.086] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 01/23/2012] [Accepted: 01/29/2012] [Indexed: 10/14/2022]
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40
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Novince CM, Michalski MN, Koh AJ, Sinder BP, Entezami P, Eber MR, Pettway GJ, Rosol TJ, Wronski TJ, Kozloff KM, McCauley LK. Proteoglycan 4: a dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism. J Bone Miner Res 2012; 27:11-25. [PMID: 21932346 PMCID: PMC4118835 DOI: 10.1002/jbmr.508] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 08/08/2011] [Accepted: 08/25/2011] [Indexed: 12/16/2022]
Abstract
Proteoglycan 4 (Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH-responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild-type mice were administered intermittent PTH(1-34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild-type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild-type mice were administered intermittent PTH(1-34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH-mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild-type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF-2) mRNA and reduced serum FGF-2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF-2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone- and liver-derived FGF-2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure.
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Affiliation(s)
- Chad M Novince
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Megan N Michalski
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Amy J Koh
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Benjamin P Sinder
- Department of Orthopaedic Surgery, Medical School, University of Michigan, Ann Arbor, MI, USA
| | - Payam Entezami
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Matthew R Eber
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Glenda J Pettway
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Thomas J Rosol
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
| | - Thomas J Wronski
- Department of Physiological Sciences, University of Florida, Gainesville, FL, USA
| | - Ken M Kozloff
- Department of Orthopaedic Surgery, Medical School, University of Michigan, Ann Arbor, MI, USA
| | - Laurie K McCauley
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, Medical School, University of Michigan, Ann Arbor, MI, USA
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41
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Datsis GA, Berdiaki A, Nikitovic D, Mytilineou M, Katonis P, Karamanos NK, Tzanakakis GN. Parathyroid hormone affects the fibroblast growth factor-proteoglycan signaling axis to regulate osteosarcoma cell migration. FEBS J 2011; 278:3782-92. [DOI: 10.1111/j.1742-4658.2011.08300.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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42
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Sharan K, Mishra JS, Swarnkar G, Siddiqui JA, Khan K, Kumari R, Rawat P, Maurya R, Sanyal S, Chattopadhyay N. A novel quercetin analogue from a medicinal plant promotes peak bone mass achievement and bone healing after injury and exerts an anabolic effect on osteoporotic bone: the role of aryl hydrocarbon receptor as a mediator of osteogenic action. J Bone Miner Res 2011; 26:2096-111. [PMID: 21638315 DOI: 10.1002/jbmr.434] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
We recently reported that extracts made from the stem bark of Ulmus wallichiana promoted peak bone mass achievement in growing rats and preserved trabecular bone mass and cortical bone strength in ovariectomized (OVX) rats. Further, 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-3',4',5,7-tetrahydroxyflavanol (GTDF), a novel flavonol-C-glucoside isolated from the extracts, had a nonestrogenic bone-sparing effect on OVX rats. Here we studied the effects of GTDF on osteoblast function and its mode of action and in vivo osteogenic effect. GTDF stimulated osteoblast proliferation, survival, and differentiation but had no effect on osteoclastic or adipocytic differentiation. In cultured osteoblasts, GTDF transactivated the aryl hydrocarbon receptor (AhR). Activation of AhR mediated the stimulatory effect of GTDF on osteoblast proliferation and differentiation. Furthermore, GTDF stimulated cAMP production, which mediated osteogenic gene expression. GTDF treatments given to 1- to 2-day-old rats or adult rats increased the mRNA levels of AhR target genes in calvaria or bone marrow stromal cells. In growing female rats, GTDF promoted parameters of peak bone accrual in the appendicular skeleton, including increased longitudinal growth, bone mineral density, bone-formation rate (BFR), cortical deposition, and bone strength. GTDF promoted the process of providing newly generated bone to fill drill holes in the femurs of both estrogen-sufficient and -deficient rats. In osteopenic OVX rats, GTDF increased BFR and significantly restored trabecular bone compared with the ovaries-intact group. Together our data suggest that GTDF stimulates osteoblast growth and differentiation via the AhR and promotes modeling-directed bone accrual, accelerates bone healing after injury, and exerts anabolic effects on osteopenic rats likely by a direct stimulatory effect on osteoprogenitors. Based on these preclinical data, clinical evaluation of GTDF as a potential bone anabolic agent is warranted.
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Affiliation(s)
- Kunal Sharan
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
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Datta NS. Osteoporotic fracture and parathyroid hormone. World J Orthop 2011; 2:67-74. [PMID: 22474638 PMCID: PMC3302045 DOI: 10.5312/wjo.v2.i8.67] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Revised: 04/19/2011] [Accepted: 06/01/2011] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis and age-related bone loss is associated with changes in bone remodeling characterized by decreased bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis. Recombinant parathyroid hormone (PTH), PTH(1-34), is an anabolic agent with proven benefits to bone strength and has been characterized as a potential therapy for skeletal repair. In spite of PTH's clinical use, safety is a major consideration for long-term treatment. Studies have demonstrated that intermittent PTH treatment enhances and accelerates the skeletal repair process via a number of mechanisms. Recent research into the molecular mechanism of PTH action on bone tissue has led to the development of PTH analogs to control osteoporotic fractures. This review summarizes a number of advances made in the field of PTH and bone fracture to combat these injuries in humans and in animal models. The ultimate goal of providing an alternative to PTH, currently the sole anabolic therapy in clinical use, to promote bone formation and improve bone strength in the aging population is yet to be achieved.
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Robling AG, Kedlaya R, Ellis SN, Childress PJ, Bidwell JP, Bellido T, Turner CH. Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology 2011; 152:2963-75. [PMID: 21652726 PMCID: PMC3138236 DOI: 10.1210/en.2011-0049] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PTH is a potent calcium-regulating factor that has skeletal anabolic effects when administered intermittently or catabolic effects when maintained at consistently high levels. Bone cells express PTH receptors, but the cellular responses to PTH in bone are incompletely understood. Wnt signaling has recently been implicated in the osteo-anabolic response to the hormone. Specifically, the Sost gene, a major antagonist of Wnt signaling, is down-regulated by PTH exposure. We investigated this mechanism by treating Sost-deficient mice and their wild-type littermates with anabolic and catabolic regimens of PTH and measuring the skeletal responses. Male Sost(+/+) and Sost(-/-) mice were injected daily with human PTH 1-34 (0, 30, or 90 μg/kg) for 6 wk. Female Sost(+/+) and Sost(-/-) mice were continuously infused with vehicle or high-dose PTH (40 μg/kg · d) for 3 wk. Dual energy x-ray absorptiometry-derived measures of intermittent PTH (iPTH)-induced bone gain were impaired in Sost(-/-) mice. Further probing revealed normal or enhanced iPTH-induced cortical bone formation rates but concomitant increases in cortical porosity among Sost(-/-) mice. Distal femur trabecular bone was highly responsive to iPTH in Sost(-/-) mice. Continuous PTH (cPTH) infusion resulted in equal bone loss in Sost(+/+) and Sost(-/-) mice as measured by dual energy x-ray absorptiometry. However, distal femur trabecular bone, but not lumbar spine trabecular bone, was spared the bone-wasting effects of cPTH in Sost(-/-) mice. These results suggest that changes in Sost expression are not required for iPTH-induced anabolism. iPTH-induced resorption of cortical bone might be overstimulated in Sost-deficient environments. Furthermore, Sost deletion protects some trabecular compartments, but not cortical compartments, from bone loss induced by high-dose PTH infusion.
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Affiliation(s)
- Alexander G Robling
- Department of Anatomy & Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS 5035, Indianapolis, Indiana 46202, USA.
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Pennisi A, Ling W, Li X, Khan S, Wang Y, Barlogie B, Shaughnessy JD, Yaccoby S. Consequences of daily administered parathyroid hormone on myeloma growth, bone disease, and molecular profiling of whole myelomatous bone. PLoS One 2010; 5:e15233. [PMID: 21188144 PMCID: PMC3004797 DOI: 10.1371/journal.pone.0015233] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2010] [Accepted: 11/01/2010] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates. METHODOLOGY/PRINCIPAL FINDINGS We tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models. PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden, which reflected the dependence of primary myeloma cells on the bone marrow microenvironment. Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts. In myelomatous bone, PTH markedly increased the number of osteoblasts and bone-formation parameters, and the number of osteoclasts was unaffected or moderately reduced. Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression. Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling; involvement of Wnt signaling was prominent. Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells, and altered expression of genes that control oxidative stress and inflammation. PTH receptors were not expressed by myeloma cells, and PTH had no effect on myeloma cell growth in vitro. CONCLUSIONS/SIGNIFICANCE We conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption and myeloma growth; mechanisms involve increased osteoblast production of anti-myeloma factors and minimized myeloma induction of inflammatory conditions.
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Affiliation(s)
- Angela Pennisi
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Wen Ling
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Xin Li
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Sharmin Khan
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Yuping Wang
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Bart Barlogie
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - John D. Shaughnessy
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
| | - Shmuel Yaccoby
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
- * E-mail:
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Gupta RR, Yoo DJ, Hebert C, Niger C, Stains JP. Induction of an osteocyte-like phenotype by fibroblast growth factor-2. Biochem Biophys Res Commun 2010; 402:258-64. [PMID: 20934405 DOI: 10.1016/j.bbrc.2010.10.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 10/04/2010] [Indexed: 01/24/2023]
Abstract
The purpose of this study was to characterize the molecular phenotype that occurs during the profound morphological shift of cultured osteogenic cells upon treatment with fibroblast growth factor-2 (FGF2). A time course of treatment with FGF2 was performed on an osteoblast cell line, primary bone marrow stromal cells and an osteocyte-like cell line. Morphologic changes were recorded, and gene profiling was carried out by real time PCR. By 8h of FGF2 treatment, there is a striking morphological shift of osteoblast and stromal cells to an elongated dendritic-like morphology that is remindful of osteocytes. In osteoblasts treated with FGF2, this morphologic shift is preceded by an induction of several osteocyte markers, including dentin matrix protein 1 (>20-fold) and E11 (>5-fold). There is a transient increase in the gene expression of sclerostin (3.5-fold) and PHEX (2.5-fold). Sclerostin regulation by FGF2 is complex, as gene expression becomes markedly inhibited by FGF2 at times points after 8h of treatment before rebounding at day 12. Analogous modulation of osteocyte markers is seen in bone marrow stromal cells and MLO-Y4 osteocyte-like cells. In conclusion, this study shows that FGF2 can regulate the transition of osteogenic cells towards the osteocyte lineage, as well as, regulate the expression of critical genes in osteocytes.
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Affiliation(s)
- Rishi R Gupta
- Department of Orthopaedics, University of Maryland, School of Medicine, Baltimore, MD 21201, USA
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Sierra OL, Towler DA. Runx2 trans-activation mediated by the MSX2-interacting nuclear target requires homeodomain interacting protein kinase-3. Mol Endocrinol 2010; 24:1478-97. [PMID: 20484411 DOI: 10.1210/me.2010-0029] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Runt-related transcription factor 2 (Runx2) and muscle segment homeobox homolog 2-interacting nuclear target (MINT) (Spen homolog) are transcriptional regulators critical for mammalian development. MINT enhances Runx2 activation of osteocalcin (OC) fibroblast growth factor (FGF) response element in an FGF2-dependent fashion in C3H10T1/2 cells. Although the MINT N-terminal RNA recognition motif domain contributes, the muscle segment homeobox homolog 2-interacting domain is sufficient for Runx2 activation. Intriguingly, Runx1 cannot replace Runx2 in this assay. To better understand this Runx2 signaling cascade, we performed structure-function analysis of the Runx2-MINT trans-activation relationship. Systematic truncation and domain swapping in Runx1:Runx2 chimeras identified that the unique Runx2 activation domain 3 (AD3), encompassed by residues 316-421, conveys MINT+FGF2 trans-activation in transfection assays. Ala mutagenesis of Runx2 Ser/Thr residues identified that S301 and T326 in AD3 are necessary for full MINT+FGF2 trans-activation. Conversely, phosphomimetic Asp substitution of these AD3 Ser/Thr residues enhanced activation by MINT. Adjacent Pro residues implicated regulation by a proline-directed protein kinase (PDPK). Systematic screening with PDPK inhibitors identified that the casein kinase-2/homeodomain-interacting protein kinase (HIPK)/dual specificity tyrosine phosphorylation regulated kinase inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), but not ERK, c-Jun N-terminal kinase, p38MAPK, or other casein kinase-2 inhibitors, abrogated Runx2-, MINT-, and FGF2-activation. Systematic small interfering RNA-mediated silencing of DMAT-inhibited PDPKs revealed that HIPK3 depletion reduced MINT+FGF2-dependent activation of Runx2. HIPK3 and Runx2 coprecipitate after in vitro transcription-translation, and recombinant HIPK3 recognizes Runx2 AD3 as kinase substrate. Furthermore, DMAT treatment and HIPK3 RNAi inhibited MINT+FGF2 activation of Runx2 AD3, and nuclear HIPK3 colocalized with MINT. HIPK3 antisense oligodeoxynucleotide selectively reduced Runx2 protein accumulation and OC gene expression in C3H10T1/2 cells. Thus, HIPK3 participates in MINT+FGF2 regulation of Runx2 AD3 activity and controls Runx2-dependent OC expression.
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Affiliation(s)
- Oscar L Sierra
- Washington University School of Medicine, Internal Medicine-Endocrinology/Metabolism, Campus Box 8301, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
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Current world literature. Curr Opin Endocrinol Diabetes Obes 2009; 16:470-80. [PMID: 19858911 DOI: 10.1097/med.0b013e3283339a46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Fibroblast growth factor 2 positively regulates expression of activating transcription factor 4 in osteoblasts. Biochem Biophys Res Commun 2009; 391:335-9. [PMID: 19913500 DOI: 10.1016/j.bbrc.2009.11.059] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Accepted: 11/09/2009] [Indexed: 11/23/2022]
Abstract
Our previous studies showed that basic fibroblast growth factor 2 (FGF2) null mice display markedly reduced bone mass and bone formation. However, the mechanism by which FGF2 regulates bone mass or bone formation is not fully defined. Activating transcription factor 4 (ATF4), one member of activating transcription factor/cAMP response element binding family, is a transcription factor required for osteoblast terminal differentiation. Here we investigate the ability of FGF2 to increase expression of ATF4 in bone marrow stromal cells (BMSCs) and examine ATF4 expression in Fgf2(-/-) BMSCs. We found that FGF2 stimulated ATF4 mRNA expression as early as 20 min and increased ATF4 protein expression after three hours of treatment. BMSCs from Fgf2(+/+) and Fgf2(-/-) mice were cultured in osteogenesis medium. We observed reduced alkaline phosphatase staining, decreased mineralized nodules and reduced osteocalcin expression, and reduced expression of ATF4 in Fgf2(-/-) BMSC cultures compared to Fgf2(+/+) BMSCs. This study is the first demonstration that ATF4 expression can be stimulated by FGF2 in osteoblasts and that ATF4 expression is significantly reduced in differentiated Fgf2(-/-) BMSCs. These results suggest that impaired bone mass and bone formation in Fgf2 null mice may be due in part to reduced ATF4 expression.
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Abstract
The Runt domain (Runx) is a 128 amino acid sequence motif that defines a metazoan family of sequence-specific DNA binding proteins, which appears to have originated in concert with the intercellular signaling systems that coordinate multicellular development in animals. In the model organisms where they have been studied (fruit fly, mouse, sea urchin, and nematode) Runx genes are essential for normal development, and in humans they are causally associated with a variety of cancers, manifesting both oncogenic and tumor suppressive attributes. During development Runx proteins support both cell proliferation and differentiation, and function in both transcriptional activation and repression. Runx function is thus context-dependent, with the context provided genetically by cis-regulatory sequence architecture and epigenetically by development. This context dependency makes it difficult to formulate reductionistic generalizations concerning Runx function in normal and carcinogenic development. However, a growing body of literature links Runx function to each of the major intercellular signaling systems in animals, suggesting that the general function of Runx transcription factors may be to potentiate and govern genomic responsiveness to developmental signaling.
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Affiliation(s)
- James A Coffman
- Mount Desert Island Biological Laboratory, Salisbury Cove, Maine 04672, USA.
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