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Wang L, Jin Y, Zhi Y, Li Z, Wang M, Wang B, Wang X. Effects of melatonin in polycystic ovary syndrome: is there Hippo pathway crosstalk? J Ovarian Res 2025; 18:101. [PMID: 40369589 PMCID: PMC12076993 DOI: 10.1186/s13048-025-01642-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 03/06/2025] [Indexed: 05/16/2025] Open
Abstract
OBJECTIVE Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder among reproductive women, characterized by hyperandrogenism, oligo-ovulation and polycystic ovarian morphology. Incorporating complementary medicine alongside traditional lifestyle therapies for PCOS may offer additional benefits for affected women. Melatonin (MT), a hormone secreted by the pineal gland, has emerged as a potential treatment for regulating ovarian function in PCOS. However, the specific effects and underlying mechanisms of MT on PCOS need to be elucidated. METHODS This review consolidates evidence from randomized controlled trials, original research articles, systematic reviews, and meta-analyses regarding MT supplementation in PCOS, with a particular focus on its interaction with the Hippo pathway, to provide a comprehensive overview of current knowledge. RESULTS Current evidence suggests that MT plays a role in modulating PCOS through various mechanisms and is associated with the Hippo pathway. However, several uncertainties and key limitations in the existing literature must be addressed before these treatments can be integrated into standard clinical practice. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Lijun Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Yuanyuan Jin
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Yuanyuan Zhi
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Zhenzhen Li
- Department of Pathology, Shandong Provincial Maternal and Child Health Care Hospital, Qingdao University, Jinan, 250014, China
| | - Meili Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
| | - Boda Wang
- Emergency Department, Xinji Town Central Health Center, Guanxian County, Liaocheng, 252500, China
| | - Xinbo Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China.
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China.
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Rong Z, Xi Y, Zhang C, Dai W, Xue H, Luo F, Xu J, Dai F. Herpesvirus-Entry Mediator Inhibits the NF- κB Pathway Activated by IL-17 and Fosters the Osteogenic Differentiation of Allogeneic Mesenchymal Stem Cells. J Tissue Eng Regen Med 2024; 2024:8146991. [PMID: 40225753 PMCID: PMC11919193 DOI: 10.1155/2024/8146991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 08/09/2024] [Indexed: 04/15/2025]
Abstract
The challenge in developing tissue-engineered bones (TEBs) for clinical applications lies in the constraints associated with the source and availability of autologous mesenchymal stem cells (MSCs) derived from the bone marrow, which creates a bottleneck. While allogeneic MSCs have shown promise in TEB applications, their ability to promote bone growth is notably diminished because of the inflammatory reaction at the transplant site and the inherent immune response triggered by allogeneic MSCs. Hence, there is a pressing need to develop methods that enhance the osteogenic differentiation of allogeneic MSCs during transplantation. Previous studies have found that IL-17 is a key proinflammatory factor in initiating inflammation and cascade amplification in the early stages of an inflammatory response, and proinflammatory cytokines such as TNF-α and IL-17 can inhibit the osteogenic differentiation of MSCs in an immune environment. In this study, MSCs expressing HVEM were successfully constructed by viral transfection and further reconfirmed that IL-17 can inhibit the in vivo and in vitro osteogenesis of allogeneic MSCs through in vitro experiments and mouse calvarial bone defect (diameter about 3 mm) model, while MSCs that express herpesvirus-entry mediator (HVEM) exhibit the capacity to suppress immune responses and sustain strong osteogenic potential. We further pointed out that the mechanism by which HVEM promotes the osteogenesis of allogeneic MSCs is related to its inhibition of the IκB kinase (IKK)-NF-κB signaling pathway activated by IL-17 in the immune environment, which can significantly inhibit the ubiquitination and degradation of β-catenin in MSCs induced by the IKK-NF-κB pathway, upregulate the expression of β-catenin, and promote bone formation. Hence, this research provides an initial connection between the Wnt/β-catenin signaling pathway and the IKK-NF-κB pathway during allogeneic MSC transplantation, offering new avenues for investigation and establishing a theoretical foundation for the potential use of HVEM-expressing MSCs in clinical treatments for bone defects.
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Affiliation(s)
- Zhigang Rong
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yuhang Xi
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Chengmin Zhang
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Wei Dai
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hao Xue
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Fei Luo
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jianzhong Xu
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
| | - Fei Dai
- Department of OrthopaedicsSouthwest HospitalThird Military Medical University (Army Medical University), Chongqing 400038, China
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Chen Y, Shi T, Li L, Hong R, Lai J, Huang T, Xu R, Zhao Q, Chen X, Dai L, Zhou Y, Liu W, Lin J. Tannic acid and quaternized chitosan mediated puerarin-loaded octacalcium phosphate /sodium alginate scaffold for bone tissue engineering. Int J Biol Macromol 2024; 271:132632. [PMID: 38797298 DOI: 10.1016/j.ijbiomac.2024.132632] [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: 02/16/2024] [Revised: 05/03/2024] [Accepted: 05/22/2024] [Indexed: 05/29/2024]
Abstract
Current limitations in mechanical performance and foreign body reactions (FBR) often lead to implant failure, restricting the application of bioceramic scaffolds. This study presents a novel 3D-printed scaffold that combines the release of anti-inflammatory drugs with osteogenic stimulation. Initially, the inorganic and organic phases were integrated to ensure the scaffold's mechanical integrity through catechol chemistry and the electrostatic interactions between tannic acid and quaternary ammonium chitosan. Subsequently, layers of polydopamine-encapsulated puerarin-loaded zeolitic imidazolate framework-8 (ZIF-8) were self-assembled onto the stent's surface, creating the drug-loaded scaffold that improved drug release without altering the scaffold's structure. Compared with unloaded scaffolds, the puerarin-loaded scaffold demonstrated excellent osteogenic differentiation properties along with superior anti-inflammatory and osteogenic effects in a range of in vitro and in vivo studies. RNA sequencing clarified the role of the TNF and NF/κB signaling pathways in these effects, further supporting the scaffold's osteogenic potential. This study introduces a novel approach for creating drug-loaded scaffolds, providing a unique method for treating cancellous bone defects.
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Affiliation(s)
- Yan Chen
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China; University of Chinese Academy of Sciences, Beijing, China
| | - Tengbin Shi
- Orthopedics Department, Fujian Medical University Union Hospital, Fuzhou, China
| | - Lan Li
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China; University of Chinese Academy of Sciences, Beijing, China
| | - Ruchen Hong
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
| | - Jun Lai
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
| | - Tingting Huang
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
| | - Rui Xu
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China; University of Chinese Academy of Sciences, Beijing, China
| | - Qing Zhao
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
| | - Xiaolong Chen
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China; University of Chinese Academy of Sciences, Beijing, China
| | - Lijun Dai
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
| | - Yuan Zhou
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
| | - Wenge Liu
- Orthopedics Department, Fujian Medical University Union Hospital, Fuzhou, China.
| | - Jinxin Lin
- Key Laboratory of Optoelectronic Materials Chemical and Physics, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.
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Sandra F, Sudiono J, Chouw A, Celinna M, Dewi NM, Djamil MS. Inhibition of lipopolysaccharide-induced NF-κB maintains osteogenesis of dental pulp and periodontal ligament stem cells. Braz Oral Res 2024; 38:e037. [PMID: 38747824 PMCID: PMC11376659 DOI: 10.1590/1807-3107bor-2024.vol38.0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 08/29/2023] [Indexed: 09/12/2024] Open
Abstract
Dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) can differentiate into osteoblasts, indicating that both are potential candidates for bone tissue engineering. Osteogenesis is influenced by many environmental factors, one of which is lipopolysaccharide (LPS). LPS-induced NF-κB activity affects the osteogenic potencies of different types of MSCs differently. This study evaluated the effect of LPS-induced NF-κB activity and its inhibition in DPSCs and PDLSCs. DPSCs and PDLSCs were cultured in an osteogenic medium, pretreated with/without NF-κB inhibitor Bay 11-7082, and treated with/without LPS. Alizarin red staining was performed to assess bone nodule formation, which was observed under an inverted light microscope. NF-κB and alkaline phosphatase (ALP) activities were measured to examine the effect of Bay 11-7082 pretreatment and LPS supplementation on osteogenic differentiation of DPSCs and PDLSCs. LPS significantly induced NF-κB activity (p = 0.000) and reduced ALP activity (p = 0.000), which inhibited bone nodule formation in DPSCs and PDLSCs. Bay 11-7082 inhibited LPS-induced NF-κB activity, and partially maintained ALP activity and osteogenic potency of LPS-supplemented DPSCs and PDLSCs. Thus, inhibition of LPS-induced NF-κB activity can maintain the osteogenic potency of DPSCs and PDLSCs.
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Affiliation(s)
- Ferry Sandra
- Universitas Trisakti, Faculty of Dentistry, Division of Oral Biology, Department of Biochemistry and Molecular Biology, Jakarta Barat, Jakarta, Indonesia
| | - Janti Sudiono
- Universitas Trisakti, Faculty of Dentistry, Division of Oral Biology, Department of Oral Pathology, Jakarta Barat, Jakarta, Indonesia
| | - Angliana Chouw
- PT Prodia StemCell Indonesia, Jakarta Pusat, Jakarta, Indonesia
| | - Maria Celinna
- The Prodia Education and Research Institute, Jakarta Pusat, Jakarta, Indonesia
| | | | - Melanie Sadono Djamil
- Universitas Trisakti, Faculty of Dentistry, Division of Oral Biology, Department of Biochemistry and Molecular Biology, Jakarta Barat, Jakarta, Indonesia
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Zhao Z, Du Y, Yan K, Zhang L, Guo Q. Exercise and osteoimmunology in bone remodeling. FASEB J 2024; 38:e23554. [PMID: 38588175 DOI: 10.1096/fj.202301508rrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 02/20/2024] [Accepted: 02/28/2024] [Indexed: 04/10/2024]
Abstract
Bones can form the scaffolding of the body, support the organism, coordinate somatic movements, and control mineral homeostasis and hematopoiesis. The immune system plays immune supervisory, defensive, and regulatory roles in the organism, which mainly consists of immune organs (spleen, bone marrow, tonsils, lymph nodes, etc.), immune cells (granulocytes, platelets, lymphocytes, etc.), and immune molecules (immune factors, interferons, interleukins, tumor necrosis factors, etc.). Bone and the immune system have long been considered two distinct fields of study, and the bone marrow, as a shared microenvironment between the bone and the immune system, closely links the two. Osteoimmunology organically combines bone and the immune system, elucidates the role of the immune system in bone, and creatively emphasizes its interdisciplinary characteristics and the function of immune cells and factors in maintaining bone homeostasis, providing new perspectives for skeletal-related field research. In recent years, bone immunology has gradually become a hot spot in the study of bone-related diseases. As a new branch of immunology, bone immunology emphasizes that the immune system can directly or indirectly affect bones through the RANKL/RANK/OPG signaling pathway, IL family, TNF-α, TGF-β, and IFN-γ. These effects are of great significance for understanding inflammatory bone loss caused by various autoimmune or infectious diseases. In addition, as an external environment that plays an important role in immunity and bone, this study pays attention to the role of exercise-mediated bone immunity in bone reconstruction.
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Affiliation(s)
- Zhonghan Zhao
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Yuxiang Du
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Kai Yan
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Lingli Zhang
- College of Athletic Performance, Shanghai University of Sport, Shanghai, China
| | - Qiang Guo
- Department of Orthopaedics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Liu F, Zhao Y, Pei Y, Lian F, Lin H. Role of the NF-kB signalling pathway in heterotopic ossification: biological and therapeutic significance. Cell Commun Signal 2024; 22:159. [PMID: 38439078 PMCID: PMC10910758 DOI: 10.1186/s12964-024-01533-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 02/13/2024] [Indexed: 03/06/2024] Open
Abstract
Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be divided into the following types of acquired and inherited ossification: traumatic HO (tHO) and fibrodysplasia ossificans progressiva (FOP). Nuclear transcription factor kappa B (NF-κB) signalling is essential during HO. NF-κB signalling can drive initial inflammation through interactions with the NOD-like receptor protein 3 (NLRP3) inflammasome, Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK). In the chondrogenesis stage, NF-κB signalling can promote chondrogenesis through interactions with mechanistic target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). NF-κB expression can modulate osteoblast differentiation by upregulating secreted protein acidic and rich in cysteine (SPARC) and interacting with mTOR signalling, bone morphogenetic protein (BMP) signalling or integrin-mediated signalling under stretch stimulation in the final osteogenic stage. In FOP, mutated ACVR1-induced NF-κB signalling exacerbates inflammation in macrophages and can promote chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signalling and mTOR signalling. This review summarizes the molecular mechanism of NF-κB signalling during HO and highlights potential therapeutics for treating HO.
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Affiliation(s)
- Fangzhou Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Yike Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Yiran Pei
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Fengyu Lian
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Hui Lin
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
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Jaffery H, Huesa C, Chilaka S, Cole J, Doonan J, Akbar M, Dunning L, Tanner KE, van ‘t Hof RJ, McInnes IB, Carmody RJ, Goodyear CS. IĸB Protein BCL3 as a Controller of Osteogenesis and Bone Health. Arthritis Rheumatol 2023; 75:2148-2160. [PMID: 37410754 PMCID: PMC10952620 DOI: 10.1002/art.42639] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 06/01/2023] [Accepted: 06/27/2023] [Indexed: 07/08/2023]
Abstract
OBJECTIVE IĸB protein B cell lymphoma 3-encoded protein (BCL3) is a regulator of the NF-κB family of transcription factors. NF-κB signaling fundamentally influences the fate of bone-forming osteoblasts and bone-resorbing osteoclasts, but the role of BCL3 in bone biology has not been investigated. The objective of this study was to evaluate BCL3 in skeletal development, maintenance, and osteoarthritic pathology. METHODS To assess the contribution of BCL3 to skeletal homeostasis, neonatal mice (n = 6-14) lacking BCL3 (Bcl3-/- ) and wild-type (WT) controls were characterized for bone phenotype and density. To reveal the contribution to bone phenotype by the osteoblast compartment in Bcl3-/- mice, transcriptomic analysis of early osteogenic differentiation and cellular function (n = 3-7) were assessed. Osteoclast differentiation and function in Bcl3-/- mice (n = 3-5) was assessed. Adult 20-week Bcl3-/- and WT mice bone phenotype, strength, and turnover were assessed. A destabilization of the medial meniscus model of osteoarthritic osteophytogenesis was used to understand adult bone formation in Bcl3-/- mice (n = 11-13). RESULTS Evaluation of Bcl3-/- mice revealed congenitally increased bone density, long bone dwarfism, increased bone biomechanical strength, and altered bone turnover. Molecular and cellular characterization of mesenchymal precursors showed that Bcl3-/- cells displayed an accelerated osteogenic transcriptional profile that led to enhanced differentiation into osteoblasts with increased functional activity, which could be reversed with a mimetic peptide. In a model of osteoarthritis-induced osteophytogenesis, Bcl3-/- mice exhibited decreased pathological osteophyte formation (P < 0.05). CONCLUSION Cumulatively, these findings demonstrate that BCL3 controls developmental mineralization to enable appropriate bone formation, whereas in a pathological setting, it contributes to skeletal pathology.
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Affiliation(s)
- Hussain Jaffery
- School of Infection & ImmunityUniversity of GlasgowGlasgowUK
| | - Carmen Huesa
- School of Infection & Immunity, University of Glasgow, Glasgow and Institute of Biomedical & Environmental Health, University of the West of ScotlandPaisleyUK
| | | | - John Cole
- School of Infection & ImmunityUniversity of GlasgowGlasgowUK
| | - James Doonan
- School of Infection & ImmunityUniversity of GlasgowGlasgowUK
| | - Moeed Akbar
- School of Infection & ImmunityUniversity of GlasgowGlasgowUK
| | - Lynette Dunning
- Institute of Biomedical & Environmental HealthUniversity of the West of ScotlandPaisleyUK
| | - Kathleen Elizabeth Tanner
- James Watt School of EngineeringUniversity of GlasgowGlasgowUK
- Present address:
School of Engineering and Materials Science and Institute of BioengineeringQueen Mary University of LondonLondonUK
| | - Rob J. van ‘t Hof
- Institute of Ageing and Chronic DiseaseUniversity of LiverpoolLiverpoolUK
| | - Iain B. McInnes
- School of Infection & ImmunityUniversity of GlasgowGlasgowUK
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Jantaboon S, Sakunrangsit N, Toejing P, Leelahavanichkul A, Pisitkun P, Greenblatt MB, Lotinun S. Lipopolysaccharide Impedes Bone Repair in FcγRIIB-Deficient Mice. Int J Mol Sci 2023; 24:16944. [PMID: 38069267 PMCID: PMC10707393 DOI: 10.3390/ijms242316944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/18/2023] Open
Abstract
Chronic inflammation contributes to the development of skeletal disorders in patients with systemic lupus erythematosus (SLE). Activation of the host immune response stimulates osteoclast activity, which in turn leads to bone loss. Regenerating bone in the inflammatory microenvironments of SLE patients with critical bone defects remains a great challenge. In this study, we utilized lipopolysaccharide (LPS) to imitate locally and systemically pathogenic bacterial infection and examined the bone regeneration performance of LPS-associated mandibular and tibial bone regeneration impairment in FcγRIIB-/- mice. Our results indicated that a loss of FcγRIIB alleviates bone regeneration in both mandibles and tibiae. After LPS induction, FcγRIIB-/- mice were susceptible to impaired fracture healing in tibial and mandibular bones. LPS decreased the mineralization to collagen ratio in FcγRIIB-/- mice, indicating a mineralization defect during bone repair. An osteoblast-associated gene (Col1a1) was attenuated in FcγRIIB-deficient mice, whereas Bglap, Hhip, and Creb5 were further downregulated with LPS treatment in FcγRIIB-/- mice compared to FcγRIIB-/- mice. Alpl and Bglap expression was dcreased in osteoblasts derived from bone chips. An osteoclast-associated gene, Tnfsf11/Tnfrsf11 ratio, ewas increased in LPS-induced FcγRIIB-/- mice and in vitro. Furthermore, systemic LPS was relatively potent in stimulating production of pro-inflammatory cytokines including TNF-α, IL-6, and MCP-1 in FcγRIIB-/- mice compared to FcγRIIB-/- mice. The levels of TNF-α, IFN-β, IL-1α, and IL-17A were increased, whereas IL-10 and IL-23 were decreased in FcγRIIB-/- mice treated locally with LPS. These findings suggest that both local and systemic LPS burden can exacerbate bone regeneration impairment, delay mineralization and skeletal repair, and induce inflammation in SLE patients.
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Affiliation(s)
- Sirikanda Jantaboon
- Interdisciplinary Program of Physiology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Nithidol Sakunrangsit
- Center of Excellence in Skeletal Disorders and Enzyme Reaction Mechanism, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand (P.T.)
| | - Parichart Toejing
- Center of Excellence in Skeletal Disorders and Enzyme Reaction Mechanism, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand (P.T.)
| | - Asada Leelahavanichkul
- Division of Immunology, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Prapaporn Pisitkun
- Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand;
| | - Matthew B. Greenblatt
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine and Research Division, Hospital for Special Surgery, New York, NY 10065, USA;
| | - Sutada Lotinun
- Center of Excellence in Skeletal Disorders and Enzyme Reaction Mechanism, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand (P.T.)
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Bighetti-Trevisan RL, Bueno NP, Souza ATP, Marques MM, Rosa AL, Beloti MM, Ferraz EP. Disruption of TNF-α signaling improves osteoblastic differentiation of adipose-derived mesenchymal stem cells and bone repair. Biotechnol Bioeng 2023; 120:3067-3078. [PMID: 37317560 DOI: 10.1002/bit.28468] [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: 03/08/2023] [Revised: 05/22/2023] [Accepted: 05/26/2023] [Indexed: 06/16/2023]
Abstract
Adipose tissue is an attractive source of mesenchymal stem cells (at-MSCs), but their low osteogenic potential limits their use in bone regeneration. Adipose tissue plays a role in pro-inflammatory diseases by releasing cytokines with a catabolic effect on bone, such as tumor necrosis factor-alpha (TNF-α). Thus, we hypothesized that endogenous TNF-α could have a negative effect on at-MSC differentiation into osteoblasts. Short interfering RNAs (siRNAs) targeting TNF-α receptors (siR1, siR2, and si1R/R2) were transfected into at-MSCs, and cell differentiation was assessed by measuring the expression of bone markers, ALP activity, and mineralized matrix. Scrambled was used as Control. Knockout at-MSCs (KOR1/R2) was injected in mice calvaria defects, and bone formation was evaluated by microtomography and histological analysis. Data were compared by Kruskal-Wallis or analysis of variance (5%). The expression of bone markers confirmed that at-MSCs differentiate less than bone marrow MSCs. In silenced cells, the expression of Alp, Runx2, and Opn was generally higher compared to Control. ALP, RUNX2, and OPN were expressed at elevated levels in silenced groups, most notably at-MSCs-siR1/R2. ALP was detected at high levels in at-MSCs-siR1/R2 and in-MSCs-siR1, followed by an increase in mineralized nodules in at-MSCs-siR1/R2. As the morphometric parameters increased, the groups treated with KOR1/R2 exhibited slight bone formation near the edges of the defects. Endogenous TNF-α inhibits osteoblast differentiation and activity in at-MSCs, and its disruption increases bone formation. While opening a path of investigation, that may lead to the development of new treatments for bone regeneration using at-MSC-based therapies.
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Affiliation(s)
- Rayana L Bighetti-Trevisan
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Natália P Bueno
- School of Dentistry, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Alann T P Souza
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Márcia M Marques
- Aachen Dental Laser Centre - Sigmund Freud University, Austria Campus Prater, Vienna, Austria
| | - Adalberto L Rosa
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Marcio M Beloti
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Emanuela P Ferraz
- Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
- School of Dentistry, University of São Paulo, São Paulo, São Paulo, Brazil
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Suzon B, Goulabchand R, Louis-Sidney F, Maria A, Najjari R, Chauvet E, Le Quellec A, Bessis D, Guilpain P. Subcutaneous tissue involvement in idiopathic inflammatory myopathies: Systematic literature review including three new cases and hypothetical mechanisms. Autoimmun Rev 2023; 22:103284. [PMID: 36736986 DOI: 10.1016/j.autrev.2023.103284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Involvement of subcutaneous tissue in idiopathic inflammatory myopathies (IIM) is poorly known. METHODS We conducted a systematic review of the literature regarding panniculitis and lipodystrophy/lipoatrophy in juvenile and adult IIM via PubMed/Medline, Embase and Scopus databases. Three local observations are included in this review. Epidemiological, clinical, paraclinical and therapeutic data were collected. RESULTS Panniculitis appears to be more common in adults than in juveniles. It was mainly localised in the upper and lower limbs. Panniculitis improved in most cases with steroids and panniculitis and myositis had a similar course in 83.3% and 72.2% of cases in juveniles and adults, respectively. Lipodystrophy appeared to be more frequent in juveniles and was only observed in dermatomyositis in both juveniles and adults. Lipodystrophy was mainly partial in juveniles and adults. The median time from myositis to the diagnosis of lipodystrophy was 6 years [0-35] and 2.5 years [0-10] in juveniles and adults, respectively. Lipodystrophy was associated with anti-TIF1 gamma auto-antibody positivity, a polycyclic/chronic course of myositis and the occurrence of calcinosis and might be an indicator of poor disease control. CONCLUSION Adipose tissue involvement, particularly lipodystrophy, occurs almost exclusively in dermatomyositis. The insidious onset and lack of awareness of the diagnosis may underestimate its prevalence. Larger studies are needed to identify possible risk factors in these patients, to better potential underlying pathophysiological process, in order to discuss potential therapeutic targets.
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Affiliation(s)
- Benoit Suzon
- Department of Internal Medicine, Martinique University Hospital, Fort-de-France, Martinique, France; EpiCliV Research Unit, University of French West Indies, Fort-de-France, Martinique, France
| | - Radjiv Goulabchand
- Department of Internal Medicine, Nîmes University Hospital, France; Institute for Regenerative Medicine and Biotherapy, INSERM U1183, Montpellier, France
| | - Fabienne Louis-Sidney
- EpiCliV Research Unit, University of French West Indies, Fort-de-France, Martinique, France; Department of Rheumatology, Martinique University Hospital, France
| | - Alexandre Maria
- Institute for Regenerative Medicine and Biotherapy, INSERM U1183, Montpellier, France; Department of Internal Medicine and Immuno-Oncologie (MedI(2)O), Montpellier University Hospital, France; Montpellier-1 University, Faculty of Medicine, France
| | - Redwann Najjari
- Department of Internal Medicine and Multi-Organic Diseases, Montpelier University Hospital, France
| | - Elodie Chauvet
- Department of Internal Medicine and Multi-Organic Diseases, Montpelier University Hospital, France
| | - Alain Le Quellec
- Department of Internal Medicine and Multi-Organic Diseases, Montpelier University Hospital, France
| | - Didier Bessis
- Department of Dermatology, Montpellier University Hospital, France
| | - Philippe Guilpain
- Institute for Regenerative Medicine and Biotherapy, INSERM U1183, Montpellier, France; Montpellier-1 University, Faculty of Medicine, France; Department of Internal Medicine and Multi-Organic Diseases, Montpelier University Hospital, France.
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11
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Mohamad-Fauzi N, Shaw C, Foutouhi SH, Hess M, Kong N, Kol A, Storey DB, Desai PT, Shah J, Borjesson D, Murray JD, Weimer BC. Salmonella enhances osteogenic differentiation in adipose-derived mesenchymal stem cells. Front Cell Dev Biol 2023; 11:1077350. [PMID: 37009487 PMCID: PMC10055666 DOI: 10.3389/fcell.2023.1077350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 02/17/2023] [Indexed: 03/17/2023] Open
Abstract
The potential of mesenchymal stem cells (MSCs) for tissue repair and regeneration has garnered great attention. While MSCs are likely to interact with microbes at sites of tissue damage and inflammation, like in the gastrointestinal system, the consequences of pathogenic association on MSC activities have yet to be elucidated. This study investigated the effects of pathogenic interaction on MSC trilineage differentiation paths and mechanisms using model intracellular pathogen Salmonella enterica ssp enterica serotype Typhimurium. The examination of key markers of differentiation, apoptosis, and immunomodulation demonstrated that Salmonella altered osteogenic and chondrogenic differentiation pathways in human and goat adipose-derived MSCs. Anti-apoptotic and pro-proliferative responses were also significantly upregulated (p < 0.05) in MSCs during Salmonella challenge. These results together indicate that Salmonella, and potentially other pathogenic bacteria, can induce pathways that influence both apoptotic response and functional differentiation trajectories in MSCs, highlighting that microbes have a potentially significant role as influencers of MSC physiology and immune activity.
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Affiliation(s)
- Nuradilla Mohamad-Fauzi
- Department of Animal Science, College of Agricultural and Environmental Sciences, University of California, Davis, Davis, CA, United States
| | - Claire Shaw
- Department of Animal Science, College of Agricultural and Environmental Sciences, University of California, Davis, Davis, CA, United States
| | - Soraya H. Foutouhi
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, Davis, CA, United States
| | - Matthias Hess
- Department of Animal Science, College of Agricultural and Environmental Sciences, University of California, Davis, Davis, CA, United States
| | - Nguyet Kong
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, Davis, CA, United States
| | - Amir Kol
- Department of Pathology, Microbiology and Immunology, University of California, Davis, Davis, CA, United States
| | - Dylan Bobby Storey
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, Davis, CA, United States
| | - Prerak T. Desai
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, Davis, CA, United States
| | - Jigna Shah
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, Davis, CA, United States
| | - Dori Borjesson
- Department of Pathology, Microbiology and Immunology, University of California, Davis, Davis, CA, United States
| | - James D. Murray
- Department of Animal Science, College of Agricultural and Environmental Sciences, University of California, Davis, Davis, CA, United States
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, Davis, CA, United States
- *Correspondence: James D. Murray, ; Bart C. Weimer,
| | - Bart C. Weimer
- Department of Population Health and Reproduction, 100K Pathogen Genome Project, Davis, CA, United States
- *Correspondence: James D. Murray, ; Bart C. Weimer,
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12
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Zhang H, Zhang Q, Yuan Z, Dong J. Non-coding RNAs in ossification of the posterior longitudinal ligament. Front Genet 2022; 13:1069575. [PMID: 36506306 PMCID: PMC9729789 DOI: 10.3389/fgene.2022.1069575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/14/2022] [Indexed: 11/25/2022] Open
Abstract
Ossification of the posterior longitudinal ligament (OPLL) is a kind of disease that involves a variety of factors leading to ectopic bone deposition of the spinal ligament. Although the detailed mechanism is not clear, genetic factors play important roles in the development of this disease. Noncoding RNA (ncRNA) refers to an RNA molecule that is not translated into a protein but participates in the regulation of gene expression. Functionally important types of ncRNA associated with OPLL include long noncoding RNA, microRNA, and circular RNA. We listed the differentially expressed ncRNAs in OPLL patients and normal controls to find the ncRNAs most relevant to the pathogenesis of the disease. The potential regulatory networks of ncRNA in OPLL cells were analyzed based on their most abundant signal transduction pathway data. The analysis of the highly connected ncRNAs in the regulatory network suggests that they play an important role in OPLL. These findings provide new directions for the study of OPLL pathogenesis and therapeutic targets. In this paper, we reviewed and analyzed the literature on ncRNAs in OPLL published in recent years, aiming to help doctors better understand and treat this disease.
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Therapeutic Effect of Melatonin in Premature Ovarian Insufficiency: Hippo Pathway Is Involved. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3425877. [PMID: 36017238 PMCID: PMC9398856 DOI: 10.1155/2022/3425877] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022]
Abstract
Objective Premature ovarian insufficiency (POI) is a female reproductive disorder of unknown etiology with no definite pathogenesis. Melatonin (MT) is an endogenous hormone synthesized mainly by pineal cells and has strong endogenous effects in regulating ovarian function. To systematically explore the pharmacological mechanism of MT on POI therapy, a literature review approach was conducted at the signaling pathways level. Methods Relevant literatures were searched and downloaded from databases, including PubMed and China National Knowledge Infrastructure, using the keywords “premature ovarian insufficiency,” “Hippo signaling pathways,” and “melatonin.” The search criteria were from 2010 to 2022. Text mining was also performed. Results MT is involved in the regulation of Hippo signaling pathway in a variety of modes and has been correlated with ovarian function. Conclusions The purpose of this review is to summarize the research progress of Hippo signaling pathways and significance of MT in POI, the potential crosstalk between MT and Hippo signaling pathways, and the prospective therapy.
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Mo Q, Zhang W, Zhu A, Backman LJ, Chen J. Regulation of osteogenic differentiation by the pro-inflammatory cytokines IL-1β and TNF-α: current conclusions and controversies. Hum Cell 2022; 35:957-971. [PMID: 35522425 DOI: 10.1007/s13577-022-00711-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/23/2022] [Indexed: 12/09/2022]
Abstract
Treatment of complex bone fracture diseases is still a complicated problem that is urged to be solved in orthopedics. In bone tissue engineering, the use of mesenchymal stromal/stem cells (MSCs) for tissue repair brings hope to the medical field of bone diseases. MSCs can differentiate into osteoblasts and promote bone regeneration. An increasing number of studies show that the inflammatory microenvironment affects the osteogenic differentiation of MSCs. It is shown that TNF-α and IL-1β play different roles in the osteogenic differentiation of MSCs via different signal pathways. The main factors that affect the role of TNF-α and IL-1β in osteogenic differentiation of MSCs include concentration and the source of stem cells (different species and different tissues). This review in-depth analyzes the roles of pro-inflammatory cytokines in the osteogenic differentiation of MSCs and reveals some current controversies to provide a reference of comprehensively understanding.
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Affiliation(s)
- Qingyun Mo
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Wei Zhang
- School of Medicine, Southeast University, Nanjing, 210009, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, Nanjing, 210096, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
| | - Aijing Zhu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Ludvig J Backman
- Department of Integrative Medical Biology, Anatomy, Umeå University, SE-901 87, Umeå, Sweden
- Department of Community Medicine and Rehabilitation, Physiotherapy, Umeå University, SE-901 87, Umeå, Sweden
| | - Jialin Chen
- School of Medicine, Southeast University, Nanjing, 210009, China.
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, Nanjing, 210096, China.
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China.
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Gholizadeh-Ghaleh Aziz S, Alipour S, Ranjbarvan P, Azari A, Babaei G, Golchin A. Critical roles of TLRs on the polarization of mesenchymal stem cells for cell therapy of viral infections: a notice for COVID-19 treatment. COMPARATIVE CLINICAL PATHOLOGY 2021; 30:119-128. [PMID: 33551714 PMCID: PMC7846495 DOI: 10.1007/s00580-021-03209-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/24/2021] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells (MSCs), as one of the leading cell-based therapy, have provided a strong link between clinical investigation and basic research. MSCs have been successfully employed in treating graft versus host disease (GvHD), autoimmune disease, and several other diseases, particularly with high immune activity. Recently, MSCs have attracted attention to treating untreatable viral infections such as severe coronavirus disease 2019 (COVID-19). Given that the Toll-like receptors (TLRs) are directly able to detect internal and external hazard signals, and their stimulation has an intense effect on the ability to grow, differentiate, migrate, and maintain MSCs, it seems stimulation of these receptors can have a direct impact on the interaction of MSCs and immune cells, altering the ability to modify immune system responses. Hence, this mini-review focused on TLRs' critical roles in the polarization of MSCs for developing MSC-based therapy in viral infections. Consequently, according to the literature review, a polarization process, mediated by TLRs concerning anti-inflammatory and proinflammatory phenotype, may be considered for MSC-therapy against viral infections.
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Affiliation(s)
- Shiva Gholizadeh-Ghaleh Aziz
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Shahriar Alipour
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Parviz Ranjbarvan
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Arezo Azari
- Department of Tissue engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghader Babaei
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ali Golchin
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Non-coding RNAs in ossification of spinal ligament. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2021; 30:801-808. [PMID: 33387048 DOI: 10.1007/s00586-020-06687-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 11/25/2020] [Accepted: 11/28/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE Ossification of the spinal ligament (OSL) is a disease characterized by progressive ectopic ossification or calcification in the tissues of spinal ligament. The molecular pathogenesis of OSL has not been clearly elucidated. Recently, ncRNAs was found to functionally participate in OSL development. This review summarized current knowledge regarding the deregulation and function of ncRNAs in OSL METHODS: Relevant studies on deregulation and function of ncRNAs in OSL were retrieved from the PubMed databases. Then, studies were manually selected for inclusion based on predefined criteria. RESULT 14 studies were reviewed, with 4 studies about high throughput sequencing and microarray of ncRNAs, 8 studies relevant to the function of ncRNAs and 2 studies regarding the ncRNAs as the biomarker of OSL. CONCLUSION ncRNA play a vital role in the ossification of spinal ligament fibrocyte, including cell osteogenesis and inflammation. ncRNAs also have potential clinical utilities as therapeutic targets, risk predication and early detection in the management of OSL. LEVEL OF EVIDENCE I Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.
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Khodabandehloo F, Taleahmad S, Aflatoonian R, Rajaei F, Zandieh Z, Nassiri-Asl M, Eslaminejad MB. Microarray analysis identification of key pathways and interaction network of differential gene expressions during osteogenic differentiation. Hum Genomics 2020; 14:43. [PMID: 33234152 PMCID: PMC7687700 DOI: 10.1186/s40246-020-00293-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/13/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Adult bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stem cells that can differentiate into three lineages. They are suitable sources for cell-based therapy and regenerative medicine applications. This study aims to evaluate the hub genes and key pathways of differentially expressed genes (DEGs) related to osteogenesis by bioinformatics analysis in three different days. The DEGs were derived from the three different days compared with day 0. RESULTS Gene expression profiles of GSE37558 were obtained from the Gene Expression Omnibus (GEO) database. A total of 4076 DEGs were acquired on days 8, 12, and 25. Gene ontology (GO) enrichment analysis showed that the non-canonical Wnt signaling pathway and lipopolysaccharide (LPS)-mediated signaling pathway were commonly upregulated DEGs for all 3 days. KEGG pathway analysis indicated that the PI3K-Akt and focal adhesion were also commonly upregulated DEGs for all 3 days. Ten hub genes were identified by CytoHubba on days 8, 12, and 25. Then, we focused on the association of these hub genes with the Wnt pathways that had been enriched from the protein-protein interaction (PPI) by the Cytoscape plugin MCODE. CONCLUSIONS These findings suggested further insights into the roles of the PI3K/AKT and Wnt pathways and their association with osteogenesis. In addition, the stem cell microenvironment via growth factors, extracellular matrix (ECM), IGF1, IGF2, LPS, and Wnt most likely affect osteogenesis by PI3K/AKT.
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Affiliation(s)
| | - Sara Taleahmad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Reza Aflatoonian
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Farzad Rajaei
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Zahra Zandieh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marjan Nassiri-Asl
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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Ko JH, Oh JY. The Effect of miR-146a on the Gene Expression of Immunoregulatory Cytokines in Human Mesenchymal Stromal Cells. Int J Mol Sci 2020; 21:ijms21186809. [PMID: 32948076 PMCID: PMC7554760 DOI: 10.3390/ijms21186809] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/12/2020] [Accepted: 09/16/2020] [Indexed: 12/02/2022] Open
Abstract
Mounting evidence indicates that microRNAs (miRNAs), including miR-146a, have an impact on the immunomodulatory activities of mesenchymal stem/stromal cells (MSCs). Suppression of inflammatory macrophage activation is one of the main immunomodulatory mechanisms of MSCs. Here, we investigated whether miR-146a in MSCs might play a role in the effects of MSCs on macrophage activation. A miRNA microarray revealed that miR-146a was the most highly upregulated miRNA in MSCs upon co-culture with activated macrophages. Inhibition of miR-146a in MSCs through miR-146a inhibitor transfection had a different effect on the expression of immunoregulatory factors secreted by MSCs. Pentraxin 3, tumor necrosis factor-inducible gene 6, and cyclooxygenase-2, which are well-known mediators of the immunomodulatory functions of MSCs, were significantly upregulated in MSCs after miR-146a knockdown. By contrast, hepatocyte growth factor and stanniocalcin 1, other immunoregulatory molecules expressed by MSCs, were downregulated by miR-146a knockdown. Consequently, the inhibition of miR-146a in MSCs did not change the overall effect of MSCs on the suppression of inflammatory macrophage activation or the induction of anti-inflammatory macrophage polarization.
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Affiliation(s)
- Jung Hwa Ko
- Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea;
| | - Joo Youn Oh
- Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea;
- Department of Ophthalmology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea
- Correspondence: ; Tel.: +82-2-2072-0027; Fax: +82-2-741-3187
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Yıldırım E, Sezer G. Clinical plasma concentration of vinpocetine does not affect osteogenic differentiation of mesenchymal stem cells. Pharmacol Rep 2020; 73:202-210. [PMID: 32865810 DOI: 10.1007/s43440-020-00153-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/17/2020] [Accepted: 08/20/2020] [Indexed: 11/30/2022]
Abstract
AIM Vinpocetine (Vin) has long been used as a medicine to treat cerebrovascular disorders and as a dietary supplement to improve cognitive functions. Previous studies have revealed that the transcription factor nuclear factor kappa B (NF-κB) activity plays an important role in osteogenic differentiation of mesenchymal stem cells (MSC). Vin inhibits NF-κB-dependent inflammatory responses; however, the effect of Vin on the osteogenic differentiation of MSCs has not been reported. In this study, we aimed to the investigate effect of Vin on the osteogenic differentiation of rat bone marrow-derived MSCs (BMSCs). METHODS We treated BMSCs with clinical plasma (0.17 µM) or higher concentrations (5 and 20 µM) of Vin with no significant effect on the cell viability. Alizarin Red S and alkaline phosphatase (ALP) stainings were used to evaluate mineralizations on days 14 and 21. Moreover, expressions of target genes were detected using qRT-PCR analysis. RESULTS Osteogenic differentiation of BMSCs did not significantly change with Vin's clinical plasma concentration, but significantly decreased with higher concentrations. Calcium mineralization, ALP staining and mRNA gene expressions of Runx2 and ALP were decreased significantly with high concentrations of Vin, paticularly on day 21. CONCLUSION Our in vitro findings suggest that clinically relevant concentration of Vin seems safe to use in elderly patients with respect to osteoporosis. On the other hand, Vin at high concentrations appears to be harmful to bone homeostasis.
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Affiliation(s)
- Esma Yıldırım
- Pharmacy Division, Ministry of Health Kayseri City Hospital, 38080, Kayseri, Turkey
| | - Gulay Sezer
- School of Medicine, Pharmacology Department, Erciyes University, 38039, Kayseri, Turkey. .,Genkok Genome and Stem Cell Centre, Erciyes University, Kayseri, Turkey.
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Heng BC, Zhang X, Aubel D, Bai Y, Li X, Wei Y, Fussenegger M, Deng X. Role of YAP/TAZ in Cell Lineage Fate Determination and Related Signaling Pathways. Front Cell Dev Biol 2020; 8:735. [PMID: 32850847 PMCID: PMC7406690 DOI: 10.3389/fcell.2020.00735] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
The penultimate effectors of the Hippo signaling pathways YAP and TAZ, are transcriptional co-activator proteins that play key roles in many diverse biological processes, ranging from cell proliferation, tumorigenesis, mechanosensing and cell lineage fate determination, to wound healing and regeneration. In this review, we discuss the regulatory mechanisms by which YAP/TAZ control stem/progenitor cell differentiation into the various major lineages that are of interest to tissue engineering and regenerative medicine applications. Of particular interest is the key role of YAP/TAZ in maintaining the delicate balance between quiescence, self-renewal, proliferation and differentiation of endogenous adult stem cells within various tissues/organs during early development, normal homeostasis and regeneration/healing. Finally, we will consider how increasing knowledge of YAP/TAZ signaling might influence the trajectory of future progress in regenerative medicine.
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Affiliation(s)
- Boon C. Heng
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
- Faculty of Science and Technology, Sunway University, Subang Jaya, Malaysia
| | - Xuehui Zhang
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, China
- National Engineering Laboratory for Digital and Material Technology of Stomatology, NMPA Key Laboratory for Dental Materials, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing, China
| | - Dominique Aubel
- IUTA Department Genie Biologique, Universite Claude Bernard Lyon 1, Villeurbanne, France
| | - Yunyang Bai
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Xiaochan Li
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yan Wei
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Martin Fussenegger
- Department of Biosystems Science and Engineering, ETH-Zürich, Basel, Switzerland
| | - Xuliang Deng
- National Engineering Laboratory for Digital and Material Technology of Stomatology, NMPA Key Laboratory for Dental Materials, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing, China
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
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Xia T, Dong S, Tian J. miR‑29b promotes the osteogenic differentiation of mesenchymal stem cells derived from human adipose tissue via the PTEN/AKT/β‑catenin signaling pathway. Int J Mol Med 2020; 46:709-717. [PMID: 32468003 PMCID: PMC7307813 DOI: 10.3892/ijmm.2020.4615] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 03/10/2020] [Indexed: 01/02/2023] Open
Abstract
Accumulating evidence has documented that microRNAs (miRNAs or miRs) function as important post-transcriptional regulators of the differentiation of mesenchymal stem cells (MSCs), including human adipose-derived mesenchymal stem cells (hADSCs); however, their roles in hADSC osteogenic differentiation require further investigation. The present study aimed to investigate the role of miRNAs in the osteogenic differentiation of hADSCs and to elucidate the underlying molecular mechanisms. Using an miRNA microarray, it was found that 24 miRNAs were upregulated and 14 miRNAs were downregulated compared with the undifferentiated cells, and miR-29b-3p (miR-29b) was selected for further experiments. Functional experiments revealed that the upregulation of miR-29b by agomir-29b significantly enhanced alkaline phosphatase (ALP) activity and the mineralization of extracellular matrix (ECM), and led to an increase in the mRNA and protein levels of osteogenic marker genes, including runt-related transcription factor 2 (Runx2), osteopontin (OPN), osteocalcin (OCN) and bone sialoprotein (BSP), whereas the knockdown of miR-29b suppressed these processes. In addition, phosphatase and tensin homolog (PTEN), a negative regulator of the AKT/β-catenin pathway, was identified as a direct target of miR-29b in the hADSCs. Moreover, it was observed that the overexpression of miR-29b activated the AKT/β-catenin signaling pathway by inhibiting PTEN expression in the hADSCs. Most importantly, it was also found that the overexpression of PTEN reversed the promoting effects of miR-29b on osteogenic differentiation. On the whole, these findings suggest that miR-29b promotes the osteogenic differentiation of hADSCs by modulating the PTEN/AKT/β-catenin signaling pathway. Thus, this miRNA may be a promising target for the active modulation of hADSC-derived osteogenesis.
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Affiliation(s)
- Tian Xia
- Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, P.R. China
| | - Shuanghai Dong
- Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, P.R. China
| | - Jiwei Tian
- Department of Orthopedics, Shanghai Jiahui International Hospital, Shanghai 200233, P.R. China
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Zhang Y, Yang C, Ge S, Wang L, Zhang J, Yang P. EphB4/ TNFR2/ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation. BMC Mol Cell Biol 2020; 21:29. [PMID: 32299362 PMCID: PMC7164363 DOI: 10.1186/s12860-020-00273-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 04/03/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Low concentrations of tumor necrosis factor-alpha (TNF-α) and its receptor TNFR2 are both reported to promote osteogenic differentiation of osteoblast precursor cells. Moreover, low concentrations of TNF-α up-regulate the expression of EphB4. However, the molecular mechanisms underlying TNF-α-induced osteogenic differentiation and the roles of TNFR2 and EphB4 have not been fully elucidated. RESULTS The ALP activity, as well as the mRNA and protein levels of RUNX2, BSP, EphB4 and TNFR2, was significantly elevated in MC3T3-E1 murine osteoblast precursor cells when stimulated with 0.5 ng/ml TNF-α. After TNFR2 was inhibited by gene knockdown with lentivirus-mediated shRNA interference or by a neutralizing antibody against TNFR2, the pro-osteogenic effect of TNF-α was partly reversed, while the up-regulation of EphB4 by TNF-α remained unchanged. With EphB4 forward signaling suppressed by a potent inhibitor of EphB4 auto-phosphorylation, NVP-BHG712, TNF-α-enhanced expressions of TNFR2, BSP and Runx2 were significantly decreased. Further investigation into the signaling pathways revealed that TNF-α significantly increased levels of p-JNK, p-ERK and p-p38. However, only the p-ERK level was significantly inhibited in TNFR2-knockdown cells. In addition, the ERK pathway inhibitor, U0126 (10 μM), significantly reversed the positive effect of TNF-α on the protein levels of RUNX2 and BSP. CONCLUSIONS The EphB4, TNFR2 and ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation.
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Affiliation(s)
- Yu Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Endodontics, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China.,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Periodontology, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China
| | - Chengzhe Yang
- Department of Oral & Maxillofacial Surgery, Qilu Hospital, Institute of Stomatology, Shandong University, No. 107 Wenhua Road West, Jinan, Shandong Province, China
| | - Shaohua Ge
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Endodontics, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China.,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Periodontology, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China
| | - Limei Wang
- Department of Oral Medicine, Qilu Hospital, Institute of Stomatology, Shandong University, No. 107 Wenhua Road West, Jinan, Shandong Province, China
| | - Jin Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Endodontics, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China. .,Department of Endodontics, School of Stomatology, Shandong University, Jinan, Shandong Province, China.
| | - Pishan Yang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Endodontics, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China. .,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Periodontology, School of Stomatology, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong Province, China.
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Jacques C, Tesfaye R, Lavaud M, Georges S, Baud’huin M, Lamoureux F, Ory B. Implication of the p53-Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas. Cells 2020; 9:cells9040810. [PMID: 32230926 PMCID: PMC7226610 DOI: 10.3390/cells9040810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 02/07/2023] Open
Abstract
The formation of the skeleton occurs throughout the lives of vertebrates and is achieved through the balanced activities of two kinds of specialized bone cells: the bone-forming osteoblasts and the bone-resorbing osteoclasts. Impairment in the remodeling processes dramatically hampers the proper healing of fractures and can also result in malignant bone diseases such as osteosarcoma. MicroRNAs (miRNAs) are a class of small non-coding single-strand RNAs implicated in the control of various cellular activities such as proliferation, differentiation, and apoptosis. Their post-transcriptional regulatory role confers on them inhibitory functions toward specific target mRNAs. As miRNAs are involved in the differentiation program of precursor cells, it is now well established that this class of molecules also influences bone formation by affecting osteoblastic differentiation and the fate of osteoblasts. In response to various cell signals, the tumor-suppressor protein p53 activates a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression.
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24
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Shioi A, Morioka T, Shoji T, Emoto M. The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification. Nutrients 2020; 12:nu12020583. [PMID: 32102248 PMCID: PMC7071387 DOI: 10.3390/nu12020583] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 02/17/2020] [Accepted: 02/20/2020] [Indexed: 12/15/2022] Open
Abstract
Vitamin K is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs) and may be implicated in cardiovascular disease (CVD). Vascular calcification is intimately associated with CV events and mortality and is a chronic inflammatory process in which activated macrophages promote osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the production of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and oncostatin M (OSM) in both intimal and medial layers of arterial walls. This process may be mainly mediated through NF-κB signaling pathway. Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Matrix Gla protein (MGP) is a major inhibitor of soft tissue calcification and contributes to preventing both intimal and medial vascular calcification. Vitamin K may also inhibit progression of vascular calcification by enhancing the activity of MGP through facilitating its γ-carboxylation. In support of this hypothesis, the procalcific effects of warfarin, an antagonist of vitamin K, on arterial calcification have been demonstrated in several clinical studies. Among the inactive MGP forms, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of not only vitamin K deficiency, but also vascular calcification and CVD. There have been several studies showing the association of circulating levels of dp-ucMGP with vitamin K intake, vascular calcification, mortality, and CVD. However, additional larger prospective studies including randomized controlled trials are necessary to confirm the beneficial effects of vitamin K supplementation on CV health.
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Affiliation(s)
- Atsushi Shioi
- Department of Vascular Medicine and Vascular Science Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan;
- Correspondence: ; Tel.: +81666453931
| | - Tomoaki Morioka
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-85858, Japan; (T.M.); (M.E.)
| | - Tetsuo Shoji
- Department of Vascular Medicine and Vascular Science Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan;
| | - Masanori Emoto
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-85858, Japan; (T.M.); (M.E.)
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25
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Liu W, Lu X, Shi P, Yang G, Zhou Z, Li W, Mao X, Jiang D, Chen C. TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway. Sci Rep 2020; 10:1804. [PMID: 32019974 PMCID: PMC7000832 DOI: 10.1038/s41598-020-58642-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/15/2020] [Indexed: 12/18/2022] Open
Abstract
Breast cancer patients often suffer from disease relapse and metastasis due to the presence of breast cancer stem-like cells (BCSCs). Numerous studies have reported that high levels of inflammatory factors, including tumor necrosis factor alpha (TNF-α), promote BCSCs. However, the mechanism by which TNF-α promotes BCSCs is unclear. In this study, we demonstrate that TNF-α up-regulates TAZ, a transcriptional co-activator promoting BCSC self-renewal capacity in human breast cancer cell lines. Depletion of TAZ abrogated the increase in BCSCs mediated by TNF-α. TAZ is induced by TNF-α through the non-canonical NF-κB pathway, and our findings suggest that TAZ plays a crucial role in inflammatory factor-promoted breast cancer stemness and could serve as a promising therapeutic target.
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Affiliation(s)
- Wenjing Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
- University of the Chinese Academy of Sciences, Beijing, 101407, China
- Medical Faculty of Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Xiaoqing Lu
- Department of breast surgery, The second hospital of Shanxi medical University, Taiyuan, 030071, China
| | - Peiguo Shi
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Guangxi Yang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Zhongmei Zhou
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Wei Li
- Medical Faculty of Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
- Department of Urology of the First People's Hospital of Yunnan Province, Kunming, 650032, China
| | - Xiaoyun Mao
- Breast surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Dewei Jiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
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26
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Burtenshaw D, Kitching M, Redmond EM, Megson IL, Cahill PA. Reactive Oxygen Species (ROS), Intimal Thickening, and Subclinical Atherosclerotic Disease. Front Cardiovasc Med 2019; 6:89. [PMID: 31428618 PMCID: PMC6688526 DOI: 10.3389/fcvm.2019.00089] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 06/14/2019] [Indexed: 12/14/2022] Open
Abstract
Arteriosclerosis causes significant morbidity and mortality worldwide. Central to this process is the development of subclinical non-atherosclerotic intimal lesions before the appearance of pathologic intimal thickening and advanced atherosclerotic plaques. Intimal thickening is associated with several risk factors, including oxidative stress due to reactive oxygen species (ROS), inflammatory cytokines and lipid. The main ROS producing systems in-vivo are reduced nicotinamide dinucleotide phosphate (NADPH) oxidase (NOX). ROS effects are context specific. Exogenous ROS induces apoptosis and senescence, whereas intracellular ROS promotes stem cell differentiation, proliferation, and migration. Lineage tracing studies using murine models of subclinical atherosclerosis have revealed the contributory role of medial smooth muscle cells (SMCs), resident vascular stem cells, circulating bone-marrow progenitors and endothelial cells that undergo endothelial-mesenchymal-transition (EndMT). This review will address the putative physiological and patho-physiological roles of ROS in controlling vascular cell fate and ROS contribution to vascular regeneration and disease progression.
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Affiliation(s)
- Denise Burtenshaw
- Vascular Biology & Therapeutics, School of Biotechnology, Dublin City University, Dublin, Ireland
| | | | - Eileen M Redmond
- Department of Surgery, University of Rochester, Rochester, NY, United States
| | - Ian L Megson
- Centre for Health Science, UHI Institute of Health Research and Innovation, Inverness, United Kingdom
| | - Paul A Cahill
- Vascular Biology & Therapeutics, School of Biotechnology, Dublin City University, Dublin, Ireland
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27
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Annamalai RT, Hong X, Schott NG, Tiruchinapally G, Levi B, Stegemann JP. Injectable osteogenic microtissues containing mesenchymal stromal cells conformally fill and repair critical-size defects. Biomaterials 2019; 208:32-44. [PMID: 30991216 PMCID: PMC6500486 DOI: 10.1016/j.biomaterials.2019.04.001] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 03/28/2019] [Accepted: 04/01/2019] [Indexed: 12/18/2022]
Abstract
Repair of complex fractures with bone loss requires a potent, space-filling intervention to promote regeneration of bone. We present a biomaterials-based strategy combining mesenchymal stromal cells (MSC) with a chitosan-collagen matrix to form modular microtissues designed for delivery through a needle to conformally fill cavital defects. Implantation of microtissues into a calvarial defect in the mouse showed that osteogenically pre-differentiated MSC resulted in complete bridging of the cavity, while undifferentiated MSC produced mineralized tissue only in apposition to native bone. Decreasing the implant volume reduced bone regeneration, while increasing the MSC concentration also attenuated bone formation, suggesting that the cell-matrix ratio is important in achieving a robust response. Conformal filling of the defect with microtissues in a carrier gel resulted in complete healing. Taken together, these results show that modular microtissues can be used to augment the differentiated function of MSC and provide an extracellular environment that potentiates bone repair.
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Affiliation(s)
- Ramkumar T Annamalai
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
| | - Xiaowei Hong
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
| | - Nicholas G Schott
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
| | | | - Benjamin Levi
- Department of Surgery, University of Michigan, Ann Arbor, United States
| | - Jan P Stegemann
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States.
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28
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Zhu Y, Li Q, Zhou Y, Li W. TLR activation inhibits the osteogenic potential of human periodontal ligament stem cells through Akt signaling in a Myd88- or TRIF-dependent manner. J Periodontol 2019; 90:400-415. [PMID: 30362568 DOI: 10.1002/jper.18-0251] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 07/06/2018] [Accepted: 07/08/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND This study investigated the effects of Toll-like receptors (TLRs) on human periodontal ligament stem cells (hPDLSCs) osteogenic differentiation and the associated mechanisms. METHODS TLR1, TLR3, TLR4, and TLR6 expression in hPDLSCs was evaluated by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and flow cytometry, whereas their functional roles were assessed based on nuclear factor (NF)-κB activation and proinflammatory cytokine expression. The osteogenic effects of these TLRs were analyzed by alkaline phosphatase (ALP) staining, ALP activity, and alizarin red staining. The roles of Myd88, TRIF, and downstream molecules mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt) in TLR-mediated impaired osteogenic differentiation were examined by real-time RT-PCR and western blotting using specific small interfering RNA siRNA and pharmacologic inhibitors. The involvement of Akt activation in restoring TLR1-, 4-, and 6-mediated osteogenic suppression was verified using the Akt activator SC-79. RESULTS TLR1, TLR3, TLR4, and TLR6 were highly expressed functionally in hPDLSCs and high doses of TLR ligands inhibited osteogenic potential. Furthermore, blocking Myd88 partly rescued the decrease in osteogenesis mediated by TLR1, TLR4, and TLR6 activation by enhancing Akt phosphorylation; likewise, TRIF suppression partially rescued lipopolysaccharide (LPS)-mediated osteogenic inhibition through ERK and Akt activation. Moreover, Akt activation restored the TLR-mediated inhibition of hPDLSC osteogenic differentiation. CONCLUSIONS High doses of TLR1, TLR4, and TLR6 ligands suppress hPDLSC osteogenic differentiation by inhibiting Akt activation through Myd88- or TRIF-dependent signaling pathways. Blocking these adaptors or reactivating Akt could restore the TLR-mediated decrease in hPDLSC osteogenesis, and might be an ideal strategy for periodontitis treatment.
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Affiliation(s)
- Yunyan Zhu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Qian Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yanheng Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Weiran Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
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29
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Ke D, Tarafder S, Vahabzadeh S, Bose S. Effects of MgO, ZnO, SrO, and SiO 2 in tricalcium phosphate scaffolds on in vitro gene expression and in vivo osteogenesis. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 96:10-19. [PMID: 30606515 PMCID: PMC6484851 DOI: 10.1016/j.msec.2018.10.073] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 09/05/2018] [Accepted: 10/21/2018] [Indexed: 11/28/2022]
Abstract
β‑tricalcium phosphate (β‑TCP) is a versatile bioceramic for its use in many orthopedic and dental applications due to its excellent biocompatibility and biodegradability. Recently, the addition of additives to β‑TCP has been proven to improve bone repair and regeneration, however, the underlying mechanism of enhanced bone regeneration is still unknown. In this study, strontium oxide (SrO), silica (SiO2), magnesia (MgO), and zinc oxide (ZnO) were added to β‑TCP for dense discs fabrication followed by in vitro evaluation using a preosteoblast cell line. Cell viability and gene expression were analyzed at day 3 and day 9 during the cell culture. MgO and SiO2 were found to significantly enhance and expedite osteoblastic differentiation. A potential mechanism was introduced to explain the additive induced osteoblastic differentiation. In addition, in vivo characterizations showed that porous 3D printed MgO-SiO2-TCP scaffolds significantly improved new bone formation after 16 weeks of implantation. This study shows beneficial effects of additives on osteoblastic viability and differentiation in vitro as well as osteogenesis in vivo, which is crucial towards the development of bone tissue engineering scaffolds.
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Affiliation(s)
- Dongxu Ke
- W. M. Keck Biomedical Materials Research Laboratory, School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99164-2920, USA
| | - Solaiman Tarafder
- W. M. Keck Biomedical Materials Research Laboratory, School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99164-2920, USA
| | - Sahar Vahabzadeh
- W. M. Keck Biomedical Materials Research Laboratory, School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99164-2920, USA
| | - Susmita Bose
- W. M. Keck Biomedical Materials Research Laboratory, School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99164-2920, USA.
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30
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Benayahu D, Wiesenfeld Y, Sapir-Koren R. How is mechanobiology involved in mesenchymal stem cell differentiation toward the osteoblastic or adipogenic fate? J Cell Physiol 2019; 234:12133-12141. [PMID: 30633367 DOI: 10.1002/jcp.28099] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 12/07/2018] [Indexed: 12/28/2022]
Abstract
Mechanobiology plays a major role in transducing physical cues from the dynamic cellular environment into biochemical modifications that promote cell-specific differentiation paths. Mesenchymal stem cells in the bone marrow or in other mesenchymal tissues will differentiate according to the expression of transcription factors (TFs) that govern their lineage commitment. The favoring of either osteogenic or adipogenic differentiation relies on TF expression as well as mechanical properties of the cells' niche that are translated into the activation of certain signaling pathways. Physical factors can induce significant shifts in bipotential lineage commitment between osteogenesis and adipogenesis. The stiffness of the extracellular matrix (ECM) surrounding a cell, varying greatly from rigid environments close to the bone surface to softer regions in the bone marrow, can influence the path of differentiation. Additionally, mechanical loading through exercise appears to favor osteogenesis whereas disuse conditions seem to promote adipogenesis.
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Affiliation(s)
- Dafna Benayahu
- Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yarden Wiesenfeld
- Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Rony Sapir-Koren
- Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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31
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Fang B, Wang D, Zheng J, Wei Q, Zhan D, Liu Y, Yang X, Wang H, Li G, He W, Xu L. Involvement of tumor necrosis factor alpha in steroid-associated osteonecrosis of the femoral head: friend or foe? Stem Cell Res Ther 2019; 10:5. [PMID: 30606261 PMCID: PMC6318982 DOI: 10.1186/s13287-018-1112-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/05/2018] [Accepted: 12/17/2018] [Indexed: 02/07/2023] Open
Abstract
Background The etiology and pathology osteonecrosis of the femoral head (ONFH) are not completely clarified. As a cytokine participating in systemic inflammation, tumor necrosis factor alpha (TNFα) has been shown to be involved in the pathogenesis of ONFH. However, the role of TNFα in ONFH is not clearly clarified. In the present study, we investigated the effects of TNFα on proliferation, angiogenesis, and osteogenic differentiation of rat bone mesenchymal stem cells (rMSCs) and the underlying mechanisms. Methods All femoral bone tissues were separated in surgeries. After extracting total RNA and protein, we evaluated TNFα content by ELISA and the relative expression levels of genes by quantitative real-time PCR and western blot. Also, immunohistochemistry staining was performed to observe the expression of Runx2 in the bone samples. Chick embryo chorioallantoic membrane (CAM) assay was performed to observe the effect of TNFα on angiogenesis. The genomic DNAs were treated by bisulfite modification, and methylation status of CpG sites in the CpG islands of human and rat Runx2 gene promoter was determined by DNA sequencing. The binding of H3K4me3 and H3K27me3 in Runx2 promoter was checked by ChIP assay. RNA-seq analysis was used to find out the genes and pathways changed by TNFα in rMSCs. Results The results demonstrate TNFα promotes cell proliferation and angiogenesis whereas inhibits osteogenesis. Epigenetic regulations including DNA methylation and histone modifications play important roles in mediating the effect of TNFα on osteogenic differentiation. We find an increased rate of CpG methylation in rat Runx2 promoter in TNFα-treated rMSCs, as well as significantly increased occupancy of H3K27me3 in Runx2 gene promoter. The content of TNFα in necrotic tissue is much lower than that of normal tissue. And relevantly, human Runx2 promoter is demethylated in necrotic tissue using bone samples from patient with ONFH. In addition, we have observed that Wnt signaling pathway is inhibited by TNFα as multiple Wnts are markedly decreased in TNFα-treated rMSCs by RNA-seq analysis. Conclusion Taken together, our study shows that TNFα plays complicated roles in the pathogenesis of ONFH, including proliferation, angiogenesis, and osteogenesis. Targeting TNFα should not be considered as an applicable strategy to inhibit the progression of ONFH. Electronic supplementary material The online version of this article (10.1186/s13287-018-1112-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Bin Fang
- Key laboratory of Orthopaedics and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China.,Department of Orthopaedics Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Baiyun District, Guangzhou, 510405, Guangdong, People's Republic of China
| | - Ding Wang
- Key laboratory of Orthopaedics and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China
| | - Jiaqian Zheng
- Key laboratory of Orthopaedics and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China
| | - Qiushi Wei
- Department of Orthopaedics Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Baiyun District, Guangzhou, 510405, Guangdong, People's Republic of China
| | - Dongxiang Zhan
- Key laboratory of Orthopaedics and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China
| | - Yamei Liu
- Departments of Diagnostics of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, People's Republic of China
| | - Xuesong Yang
- Division of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou, 510632, People's Republic of China
| | - Haibin Wang
- Key laboratory of Orthopaedics and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China.,Department of Orthopaedics Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Baiyun District, Guangzhou, 510405, Guangdong, People's Republic of China
| | - Gang Li
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region of China.
| | - Wei He
- Key laboratory of Orthopaedics and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China. .,Department of Orthopaedics Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Baiyun District, Guangzhou, 510405, Guangdong, People's Republic of China. .,Laboratory of Orthopaedics and Traumatology, Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.
| | - Liangliang Xu
- Key laboratory of Orthopaedics and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China. .,Department of Orthopaedics Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Baiyun District, Guangzhou, 510405, Guangdong, People's Republic of China. .,Laboratory of Orthopaedics and Traumatology, Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.
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Zhu X, Yu J, Du J, Zhong G, Qiao L, Lin J. LncRNA HOXA-AS2 positively regulates osteogenesis of mesenchymal stem cells through inactivating NF-κB signalling. J Cell Mol Med 2018; 23:1325-1332. [PMID: 30536618 PMCID: PMC6349193 DOI: 10.1111/jcmm.14034] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/04/2018] [Accepted: 10/27/2018] [Indexed: 12/14/2022] Open
Abstract
As is previously reported, mesenchymal stem cells have potential ability to differentiate into osteocytes. However, the underlying mechanism during this biological process is poorly understood. In the present study, we identify a novel long non-coding RNA named HOXA-AS2 as a critical regulator during the formation of osteogenesis. Attenuation of HOXA-AS2 can reduce the calcium deposition and repress the alkaline phosphatase activity. Moreover, the expressions of osteogenic marker genes are markedly downregulated after HOXA-AS2 depletion. Mechanistically, we found HOXA-AS2 can regulate the transcriptional activity of NF-κB, a critical inhibitor of osteogenesis. More importantly, HOXA-AS2 knockdown could result in the transcriptional repression of the osteogenic master transcription factor SP7 by a NF-κB/HDAC2-coordinated H3K27 deacetylation mechanism. Based on these studies, we conclude that HOXA-AS2 may serve as a promising therapeutic target for bone tissue repair and regeneration in the near future.
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Affiliation(s)
- Xinxing Zhu
- Henan Joint International Research Laboratory of Stem Cell Medicine, College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, China.,Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Jinjin Yu
- School of Psychology, Xinxiang Medical University, Xinxiang, China
| | - Jiang Du
- Henan Joint International Research Laboratory of Stem Cell Medicine, College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, China.,Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Genshen Zhong
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Liang Qiao
- Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Juntang Lin
- Henan Joint International Research Laboratory of Stem Cell Medicine, College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, China.,Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
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Lin T, Pajarinen J, Kohno Y, Huang JF, Maruyama M, Romero-Lopez M, Nathan K, Yao Z, Goodman SB. Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation. FASEB J 2018; 33:4203-4211. [PMID: 30521384 DOI: 10.1096/fj.201801845r] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Mesenchymal stem cell (MSC)-mediated immunomodulation affects both innate and adaptive immune systems. These responses to environmental cues, such as pathogen-associated molecular patterns, damage-associated molecular patterns, or proinflammatory cytokines, are crucial for resolution of inflammation, as well as successful tissue healing and regeneration. We observed that intermittent, repeated exposure of MSCs to LPS induced stronger NF-κB activation than singular stimulation. A similar phenomenon, named innate immune memory or trained immunity, has been reported with macrophages. However, the potential regulation of "immune memory" in nonclassic immune cells, such as MSCs, has not been reported. In the current study, we chose IFN-γ plus TNF-α restimulation-induced iNOS expression as a model of MSC activation, because IFN-γ and TNF-α play crucial roles in MSC-mediated immunomodulation. The iNOS expression was enhanced in LPS-trained MSCs, 3 d after a washout period following primary stimulation. LPS-trained MSCs enhanced the anti-inflammatory (arginase 1 and CD206) marker expression, but decreased the proinflammatory marker (TNF-α, IL-1β, iNOS, and IL-6) expression using an MSC-macrophage coculture model. In contrast, LPS-trained MSCs demonstrated a defective regulation on CD4 T-cell proliferation. Mechanistic studies suggested that histone methylation and the JNK pathway are involved in LPS-trained immunomodulation in MSCs. Our results demonstrate differential immunomodulatory effects of trained MSCs on macrophages and T cells. These immunomodulatory consequences are critical, because they will have a major impact on current MSC-based cell therapies.-Lin, T., Pajarinen, J., Kohno, Y., Huang, J.-F., Maruyama, M., Romero-Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation.
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Affiliation(s)
- Tzuhua Lin
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and
| | - Jukka Pajarinen
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and
| | - Yusuke Kohno
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and
| | - Jhih-Fong Huang
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and
| | - Masahiro Maruyama
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and
| | - Monica Romero-Lopez
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and
| | - Karthik Nathan
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and
| | - Zhenyu Yao
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA; and.,Department of Bioengineering, Stanford University, Stanford, California, USA
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Wang Y, Xu X, Maglic D, Dill MT, Mojumdar K, Ng PKS, Jeong KJ, Tsang YH, Moreno D, Bhavana VH, Peng X, Ge Z, Chen H, Li J, Chen Z, Zhang H, Han L, Du D, Creighton CJ, Mills GB, Camargo F, Liang H. Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer. Cell Rep 2018; 25:1304-1317.e5. [PMID: 30380420 PMCID: PMC6326181 DOI: 10.1016/j.celrep.2018.10.001] [Citation(s) in RCA: 336] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 08/02/2018] [Accepted: 09/28/2018] [Indexed: 01/15/2023] Open
Abstract
Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional "omic" data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.
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Affiliation(s)
- Yumeng Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xiaoyan Xu
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathophysiology, College of Basic Medicine Science, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Dejan Maglic
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA
| | - Michael T Dill
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA
| | - Kamalika Mojumdar
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Patrick Kwok-Shing Ng
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kang Jin Jeong
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yiu Huen Tsang
- Department of Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Daniela Moreno
- Department of Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Xinxin Peng
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhongqi Ge
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Hu Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jun Li
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhongyuan Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Statistics, Rice University, Houston, TX 77005, USA
| | - Huiwen Zhang
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA
| | - Leng Han
- Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA
| | - Di Du
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chad J Creighton
- Duncan Cancer Center-Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Gordon B Mills
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Fernando Camargo
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
| | - Han Liang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Lata M, Hettinghouse AS, Liu CJ. Targeting tumor necrosis factor receptors in ankylosing spondylitis. Ann N Y Acad Sci 2018; 1442:5-16. [PMID: 30008173 DOI: 10.1111/nyas.13933] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/19/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023]
Abstract
Over the past two decades, considerable advances in our understanding of inflammatory and immune pathways have allowed for the growing use of targeted biologic therapy. Most notably, the introduction of tumor necrosis factor (TNF) inhibitors has dramatically changed the management of autoimmune inflammatory disorders, including ankylosing spondylitis (AS). Despite the efficacy of TNF inhibitors documented in multiple clinical trials, anti-TNF therapy in AS is far from foolproof; it is associated with serious adverse effects and limited response to therapy in some patients. Moreover, specific questions regarding the role of TNF as a mediator of AS remain unanswered. Therefore, additional efforts are needed in order to better understand the role of TNF in the pathogenesis of AS and to develop safer and more effective treatment strategies. The purpose of this review is to better the understanding of the physiologic and pathogenic roles of TNF signaling in the course of AS. Relevant TNF biology and novel approaches to TNF blockade in AS are discussed.
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Affiliation(s)
- Michal Lata
- Department of Orthopedic Surgery, New York University Medical Center, Hospital for Joint Diseases, New York, New York
| | - Aubryanna S Hettinghouse
- Department of Orthopedic Surgery, New York University Medical Center, Hospital for Joint Diseases, New York, New York
| | - Chuan-Ju Liu
- Department of Orthopedic Surgery, New York University Medical Center, Hospital for Joint Diseases, New York, New York.,Department of Cell Biology, New York University School of Medicine, New York, New York
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Lv Y, Kim K, Sheng Y, Cho J, Qian Z, Zhao YY, Hu G, Pan D, Malik AB, Hu G. YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circ Res 2018; 123:43-56. [PMID: 29794022 PMCID: PMC6014930 DOI: 10.1161/circresaha.118.313143] [Citation(s) in RCA: 161] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 05/16/2018] [Accepted: 05/21/2018] [Indexed: 01/05/2023]
Abstract
RATIONALE Microvascular inflammation and endothelial dysfunction secondary to unchecked activation of endothelium play a critical role in the pathophysiology of sepsis and organ failure. The intrinsic signaling mechanisms responsible for dampening excessive activation of endothelial cells are not completely understood. OBJECTIVE To determine the central role of YAP (Yes-associated protein), the major transcriptional coactivator of the Hippo pathway, in modulating the strength and magnitude of endothelial activation and vascular inflammation. METHODS AND RESULTS Endothelial-specific YAP knockout mice showed increased basal expression of E-selectin and ICAM (intercellular adhesion molecule)-1 in endothelial cells, a greater number of adherent neutrophils in postcapillary venules and increased neutrophil counts in bronchoalveolar lavage fluid. Lipopolysaccharide challenge of these mice augmented NF-κB (nuclear factor-κB) activation, expression of endothelial adhesion proteins, neutrophil and monocyte adhesion to cremaster muscle venules, transendothelial neutrophil migration, and lung inflammatory injury. Deletion of YAP in endothelial cells also markedly augmented the inflammatory response and cardiovascular dysfunction in a polymicrobial sepsis model induced by cecal ligation and puncture. YAP functioned by interacting with the E3 ubiquitin-protein ligase TLR (Toll-like receptor) signaling adaptor TRAF6 (tumor necrosis factor receptor-associated factor 6) to ubiquitinate TRAF6, and thus promoted TRAF6 degradation and modification resulting in inhibition of NF-κB activation. TRAF6 depletion in endothelial cells rescued the augmented inflammatory phenotype in mice with endothelial cell-specific deletion of YAP. CONCLUSIONS YAP modulates the activation of endothelial cells and suppresses vascular inflammation through preventing TRAF6-mediated NF-κB activation and is hence essential for limiting the severity of sepsis-induced inflammation and organ failure.
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Affiliation(s)
- Yang Lv
- From the Department of Anesthesiology (Y.L., Guochang Hu)
- University of Illinois College of Medicine, Chicago; Department of Pharmacology, Nanjing Medical University, Jiangsu, China (Y.L., Gang Hu)
| | - Kyungho Kim
- Department of Pharmacology (K.K., J.C., A.B.M., Guochang Hu)
| | - Yue Sheng
- Department of Medicine and Cancer Research Center, The University of Illinois Hospital and Health Sciences System, Chicago (Y.S., Z.Q.)
| | - Jaehyung Cho
- Department of Pharmacology (K.K., J.C., A.B.M., Guochang Hu)
| | - Zhijian Qian
- Department of Medicine and Cancer Research Center, The University of Illinois Hospital and Health Sciences System, Chicago (Y.S., Z.Q.)
| | - You-Yang Zhao
- Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, IL (Y.-Y.Z.)
- Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, IL (Y.-Y.Z.)
- Departments of Pediatrics and Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (Y.-Y.Z.)
| | - Gang Hu
- University of Illinois College of Medicine, Chicago; Department of Pharmacology, Nanjing Medical University, Jiangsu, China (Y.L., Gang Hu)
| | - Duojia Pan
- Howard Hughes Medical Institute and Department of Physiology, UT Southwestern Medical Center, Dallas, TX (D.P.)
| | - Asrar B Malik
- Department of Pharmacology (K.K., J.C., A.B.M., Guochang Hu)
| | - Guochang Hu
- From the Department of Anesthesiology (Y.L., Guochang Hu)
- Department of Pharmacology (K.K., J.C., A.B.M., Guochang Hu)
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Paine A, Ritchlin C. Altered Bone Remodeling in Psoriatic Disease: New Insights and Future Directions. Calcif Tissue Int 2018; 102:559-574. [PMID: 29330560 PMCID: PMC5906143 DOI: 10.1007/s00223-017-0380-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 12/27/2017] [Indexed: 12/15/2022]
Abstract
Psoriatic arthritis (PsA) is an inflammatory rheumatic disorder that occurs in patients with psoriasis and predominantly affects musculoskeletal structures, skin, and nails. The etiology of PsA is not well understood but evidence supports an interplay of genetic, immunologic, and environmental factors which promote pathological bone remodeling and joint damage in PsA. Localized and systemic bone loss due to increased activity of osteoclasts is well established in PsA based on animal models and translational studies. In contrast, the mechanisms responsible for pathological bone remodeling in PsA remain enigmatic although new candidate molecules and pathways have been identified. Recent reports have revealed novel findings related to bone erosion and pathologic bone formation in PsA. Many associated risk factors and contributing molecular mechanisms have also been identified. In this review, we discuss new developments in the field, point out unresolved questions regarding the pathogenetic origins of the wide array of bone phenotypes in PsA, and discuss new directions for investigation.
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Affiliation(s)
- Ananta Paine
- Allergy, Immunology & Rheumatology Division, University of Rochester Medical Center, Rochester, NY, 14623, USA.
| | - Christopher Ritchlin
- Allergy, Immunology & Rheumatology Division, University of Rochester Medical Center, Rochester, NY, 14623, USA
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Chen X, Liu Y, Ding W, Shi J, Li S, Liu Y, Wu M, Wang H. Mechanical stretch-induced osteogenic differentiation of human jaw bone marrow mesenchymal stem cells (hJBMMSCs) via inhibition of the NF-κB pathway. Cell Death Dis 2018; 9:207. [PMID: 29434225 PMCID: PMC5833399 DOI: 10.1038/s41419-018-0279-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 11/28/2017] [Accepted: 12/27/2017] [Indexed: 01/26/2023]
Abstract
Severe malocclusion can contribute to several serious dental and physical conditions, such as digestive difficulties, periodontal disease, and severe tooth decay. Orthodontic treatment is mainly used to treat malocclusion. Forces in orthodontic tooth results in bone resorption on the pressure side and bone deposition on the tension side. Osteoblasts have been considered as the key component in bone regeneration on the tension side. However, the underlying mechanisms remain unclear. In this study, we focus on how mechanical stretch regulates the osteogenesis during orthodontic treatment. Human jaw bone marrow mesenchymal stem cells (hJBMMSCs) were isolated from healthy adult donors and cultured in regular medium (control) or osteogenic medium (OS). Under OS culture, hJBMMSCs presented osteogenic differentiation potentials, as evidenced by increased mineralization, enhanced calcium deposition, and upregulated expression of osteogenesis markers (ALP, osterix, and Runx). What's more, the OS-induced osteogenesis of hJBMMSCs is associated with the dephosphorylation of IKK, activation of IKBα, and phosphorylation/nucleic accumulation of P65, which all indicated the inhibition of NF-κB activity. Overexpressing P65 in hJBMMSCs, which could constantly activate NF-κB, prevented the osteogenic differentiation in the OS. After that, we applied the Flexcell tension system, which could cause mechanical stretch on cultured hJBMMSCs to mimic the tension forces during tooth movement. Mechanical stretch resulted in 3.5-fold increase of ALP activity and 2.4-fold increase of calcium deposition after 7 days and 21 days treatment, respectively. The expression levels of ALP, Run×2, and Osterix were also significantly upregulated. In the meantime, applying mechanical stretch on OS-cultured hJBMMSCs also dramatically promoted the OS-induced osteogenesis. Both OS and mechanical stretch downregulated NF-κB activity. By overexpressing P65 in hJBMMSCs, neither OS nor mechanical stretch could induce their osteogenesis. These results indicated that, like OS induction, mechanical stretch-facilitated osteogenesis of hJBMMSCs by inhibiting NF-κB in the noninflammatory environments.
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Affiliation(s)
- Xiaoyan Chen
- Department of Orthodontics, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yuan Liu
- Department of Liver Surgery, Ren Ji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wanghui Ding
- Department of Orthodontics, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Jiejun Shi
- Department of Orthodontics, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Shenglai Li
- Department of Oral Surgery, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yali Liu
- Department of Orthodontics, Affiliated Hospital of Stomatology, Kunming Medical University, Kunming, Yunnan Province, China
| | - Mengjie Wu
- Department of Orthodontics, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Huiming Wang
- Department of Oral Implantology, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang Province, China.
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Lin T, Pajarinen J, Nabeshima A, Lu L, Nathan K, Jämsen E, Yao Z, Goodman SB. Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis. Stem Cell Res Ther 2017; 8:277. [PMID: 29212557 PMCID: PMC5719931 DOI: 10.1186/s13287-017-0730-z] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 11/17/2017] [Accepted: 11/21/2017] [Indexed: 12/18/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) are capable of immunomodulation and tissue regeneration, highlighting their potential translational application for treating inflammatory bone disorders. MSC-mediated immunomodulation is regulated by proinflammatory cytokines and pathogen-associated molecular patterns such as lipopolysaccharide (LPS). Previous studies showed that MSCs exposed to interferon gamma (IFN-γ) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) synergistically suppressed T-cell activation. Methods In the current study, we developed a novel preconditioning strategy for MSCs using LPS plus TNF-α to optimize the immunomodulating ability of MSCs on macrophage polarization. Results Preconditioned MSCs enhanced anti-inflammatory M2 macrophage marker expression (Arginase 1 and CD206) and decreased inflammatory M1 macrophage marker (TNF-α/IL-1Ra) expression using an in-vitro coculture model. Immunomodulation of MSCs on macrophages was significantly increased compared to the combination of IFN-γ plus TNF-α or single treatment controls. Increased osteogenic differentiation including alkaline phosphate activity and matrix mineralization was only observed in the LPS plus TNF-α preconditioned MSCs. Mechanistic studies showed that increased prostaglandin E2 (PGE2) production was associated with enhanced Arginase 1 expression. Selective cyclooxygenase-2 inhibition by Celecoxib decreased PGE2 production and Arginase 1 expression in cocultured macrophages. Conclusions The novel preconditioned MSCs have increased immunomodulation and bone regeneration potential and could be applied to the treatment of inflammatory bone disorders including periprosthetic osteolysis, fracture healing/nonunions, and osteonecrosis. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0730-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tzuhua Lin
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA
| | - Jukka Pajarinen
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA
| | - Akira Nabeshima
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA
| | - Laura Lu
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA
| | - Karthik Nathan
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA
| | - Eemeli Jämsen
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA
| | - Zhenyu Yao
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA. .,Bioengineering, Stanford University, Stanford, CA, USA.
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Paduano F, Marrelli M, Amantea M, Rengo C, Rengo S, Goldberg M, Spagnuolo G, Tatullo M. Adipose Tissue as a Strategic Source of Mesenchymal Stem Cells in Bone Regeneration: A Topical Review on the Most Promising Craniomaxillofacial Applications. Int J Mol Sci 2017; 18:ijms18102140. [PMID: 29027958 PMCID: PMC5666822 DOI: 10.3390/ijms18102140] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/11/2017] [Accepted: 10/11/2017] [Indexed: 01/01/2023] Open
Abstract
Bone regeneration in craniomaxillofacial surgery represents an issue that involves both surgical and aesthetic aspects. The most recent studies on bone tissue engineering involving adipose-derived stromal/stem cells (ASCs) have clearly demonstrated that such cells can play a crucial role in the treatment of craniomaxillofacial defects, given their strong commitment towards the osteogenic phenotype. A deeper knowledge of the molecular mechanisms underlying ASCs is crucial for a correct understanding of the potentialities of ASCs-based therapies in the most complex maxillofacial applications. In this topical review, we analyzed the molecular mechanisms of ASCs related to their support toward angiogenesis and osteogenesis, during bone regeneration. Moreover, we analyzed both case reports and clinical trials reporting the most promising clinical applications of ASCs in the treatment of craniomaxillofacial defects. Our study aimed to report the main molecular and clinical features shown by ASCs, used as a therapeutic support in bone engineering, as compared to the use of conventional autologous and allogeneic bone grafts.
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Affiliation(s)
- Francesco Paduano
- Biomedical Section, Stem Cells Unit, Tecnologica Research Institute, 88900 Crotone, Italy;
| | - Massimo Marrelli
- Unit of Craniomaxillofacial Surgery, Calabrodental, 88900 Crotone, Italy;
| | | | - Carlo Rengo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, 80138 Naples, Italy; (C.R.); (S.R.); (G.S.)
| | - Sandro Rengo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, 80138 Naples, Italy; (C.R.); (S.R.); (G.S.)
| | - Michel Goldberg
- Professeur Emerite, Biomédicale des Saints Pères, Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale UMR-S 1124, 75654 Paris, France;
| | - Gianrico Spagnuolo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, 80138 Naples, Italy; (C.R.); (S.R.); (G.S.)
| | - Marco Tatullo
- Biomedical Section, Stem Cells Unit, Tecnologica Research Institute, 88900 Crotone, Italy;
- Correspondence: ; Tel.: +39-34-9874-2445
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Shen G, Ren H, Qiu T, Zhang Z, Zhao W, Yu X, Huang J, Tang J, Liang D, Yao Z, Yang Z, Jiang X. Mammalian target of rapamycin as a therapeutic target in osteoporosis. J Cell Physiol 2017; 233:3929-3944. [PMID: 28834576 DOI: 10.1002/jcp.26161] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 08/21/2017] [Indexed: 12/19/2022]
Abstract
The mechanistic target of rapamycin (mTOR) plays a key role in sensing and integrating large amounts of environmental cues to regulate organismal growth, homeostasis, and many major cellular processes. Recently, mounting evidences highlight its roles in regulating bone homeostasis, which sheds light on the pathogenesis of osteoporosis. The activation/inhibition of mTOR signaling is reported to positively/negatively regulate bone marrow mesenchymal stem cells (BMSCs)/osteoblasts-mediated bone formation, adipogenic differentiation, osteocytes homeostasis, and osteoclasts-mediated bone resorption, which result in the changes of bone homeostasis, thereby resulting in or protect against osteoporosis. Given the likely importance of mTOR signaling in the pathogenesis of osteoporosis, here we discuss the detailed mechanisms in mTOR machinery and its association with osteoporosis therapy.
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Affiliation(s)
- Gengyang Shen
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui Ren
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ting Qiu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhida Zhang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wenhua Zhao
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiang Yu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinjing Huang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingjing Tang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - De Liang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhensong Yao
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhidong Yang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaobing Jiang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Laboratory Affiliated to National Key Discipline of Orthopaedic and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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42
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Lo Sardo F, Muti P, Blandino G, Strano S. Melatonin and Hippo Pathway: Is There Existing Cross-Talk? Int J Mol Sci 2017; 18:ijms18091913. [PMID: 28878191 PMCID: PMC5618562 DOI: 10.3390/ijms18091913] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 08/30/2017] [Accepted: 09/01/2017] [Indexed: 12/16/2022] Open
Abstract
Melatonin is an indolic hormone that regulates a plethora of functions ranging from the regulation of circadian rhythms and antioxidant properties to the induction and maintenance of tumor suppressor pathways. It binds to specific receptors as well as to some cytosolic proteins, leading to several cellular signaling cascades. Recently, the involvement of melatonin in cancer insurgence and progression has clearly been demonstrated. In this review, we will first describe the structure and functions of melatonin and its receptors, and then discuss both molecular and epidemiological evidence on melatonin anticancer effects. Finally, we will shed light on potential cross-talk between melatonin signaling and the Hippo signaling pathway, along with the possible implications for cancer therapy.
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Affiliation(s)
- Federica Lo Sardo
- Oncogenomic and Epigenetic Unit, Molecular Chemoprevention Group, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
| | - Paola Muti
- Department of Oncology, Juravinski Cancer Center, McMaster University, Hamilton, ON L8S 4L8, Canada.
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, Molecular Chemoprevention Group, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
| | - Sabrina Strano
- Oncogenomic and Epigenetic Unit, Molecular Chemoprevention Group, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
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Zhang JR, Pang DD, Tong Q, Liu X, Su DF, Dai SM. Different Modulatory Effects of IL-17, IL-22, and IL-23 on Osteoblast Differentiation. Mediators Inflamm 2017; 2017:5950395. [PMID: 28831209 PMCID: PMC5555000 DOI: 10.1155/2017/5950395] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 06/04/2017] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES To examine the expressions of IL-17, IL-22, and IL-23 receptors in four osteoblast models and the effects of IL-17, IL-22, and IL-23 on osteoblasts. METHODS Gene expression levels of receptors, alkaline phosphatase (ALP), osteocalcin (OCN), and Runt-related transcription factor 2 (Runx-2), were evaluated by RT-PCR and real-time RT-PCR. Proliferative responses and cell cycle analysis were detected by a CCK-8 assay and flow cytometry, respectively. ALP activity and ALP mass were detected by an ALP activity assay and ALP staining, respectively. RESULTS In primary osteoblasts, only the IL-17 receptor was expressed. In C2C12, MC3T3-E1, and Saos-2 cells, the genes of IL-17, IL-22, and IL-23 receptors were not detectable. None of IL-17, IL-22, and IL-23 had an obvious effect on the proliferation of primary osteoblasts, but IL-17 exhibited an inhibitory effect on the gene expression of ALP, OCN, and Runx-2. The ALP activity and ALP mass of primary osteoblasts were downregulated by IL-17 treatment in a dose-dependent manner, and IL-17 failed to inhibit BMP-2-induced phosphorylation of Smad. CONCLUSION Primary osteoblasts constitutively express IL-17 receptors, but none of C2C12 cells, MC3T3-E1 cells, and Saos-2 cells express any receptors for IL-17, IL-22, and IL-23. IL-17 inhibits BMP-2-induced osteoblast differentiation via the BMP/Smad-independent pathway.
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Affiliation(s)
- Jing-Ru Zhang
- Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, Shanghai, China
- Department of Rheumatology & Immunology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, China
| | - Dan-Dan Pang
- Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qiang Tong
- Department of Rheumatology & Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xia Liu
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Ding-Feng Su
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Sheng-Ming Dai
- Department of Rheumatology & Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Miranda MZ, Bialik JF, Speight P, Dan Q, Yeung T, Szászi K, Pedersen SF, Kapus A. TGF-β1 regulates the expression and transcriptional activity of TAZ protein via a Smad3-independent, myocardin-related transcription factor-mediated mechanism. J Biol Chem 2017; 292:14902-14920. [PMID: 28739802 DOI: 10.1074/jbc.m117.780502] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 06/30/2017] [Indexed: 12/20/2022] Open
Abstract
Hippo pathway transcriptional coactivators TAZ and YAP and the TGF-β1 (TGFβ) effector Smad3 regulate a common set of genes, can physically interact, and exhibit multilevel cross-talk regulating cell fate-determining and fibrogenic pathways. However, a key aspect of this cross-talk, TGFβ-mediated regulation of TAZ or YAP expression, remains uncharacterized. Here, we show that TGFβ induces robust TAZ but not YAP protein expression in both mesenchymal and epithelial cells. TAZ levels, and to a lesser extent YAP levels, also increased during experimental kidney fibrosis. Pharmacological or genetic inhibition of Smad3 did not prevent the TGFβ-induced TAZ up-regulation, indicating that this canonical pathway is dispensable. In contrast, inhibition of p38 MAPK, its downstream effector MK2 (e.g. by the clinically approved antifibrotic pirferidone), or Akt suppressed the TGFβ-induced TAZ expression. Moreover, TGFβ elevated TAZ mRNA in a p38-dependent manner. Myocardin-related transcription factor (MRTF) was a central mediator of this effect, as MRTF silencing/inhibition abolished the TGFβ-induced TAZ expression. MRTF overexpression drove the TAZ promoter in a CC(A/T-rich)6GG (CArG) box-dependent manner and induced TAZ protein expression. TGFβ did not act by promoting nuclear MRTF translocation; instead, it triggered p38- and MK2-mediated, Nox4-promoted MRTF phosphorylation and activation. Functionally, higher TAZ levels increased TAZ/TEAD-dependent transcription and primed cells for enhanced TAZ activity upon a second stimulus (i.e. sphingosine 1-phosphate) that induced nuclear TAZ translocation. In conclusion, our results uncover an important aspect of the cross-talk between TGFβ and Hippo signaling, showing that TGFβ induces TAZ via a Smad3-independent, p38- and MRTF-mediated and yet MRTF translocation-independent mechanism.
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Affiliation(s)
- Maria Zena Miranda
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.,Biochemistry, University of Toronto, Toronto, Ontario M5B 1T8N, Canada and
| | - Janne Folke Bialik
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.,the Department of Cell and Developmental Biology, University of Copenhagen, Copenhagen DK-2100, Denmark
| | - Pam Speight
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital
| | - Qinghong Dan
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital
| | - Tony Yeung
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital
| | - Katalin Szászi
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.,Departments of Surgery and
| | - Stine F Pedersen
- the Department of Cell and Developmental Biology, University of Copenhagen, Copenhagen DK-2100, Denmark
| | - András Kapus
- From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, .,Biochemistry, University of Toronto, Toronto, Ontario M5B 1T8N, Canada and.,Departments of Surgery and
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Xiao F, Zheng R, Yang D, Cao K, Zhang S, Wu B, Shao Y, Zhou B. Sex-dependent aortic valve pathology in patients with rheumatic heart disease. PLoS One 2017; 12:e0180230. [PMID: 28662157 PMCID: PMC5491156 DOI: 10.1371/journal.pone.0180230] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 06/12/2017] [Indexed: 12/15/2022] Open
Abstract
Background Rheumatic heart disease is an autoimmune disease caused by group A streptococci infection and frequently affects the aortic valve. Sex differences are common in the disease progression, treatment, and outcome. However, little is known about the sex differences in the pathology of aortic valves in rheumatic heart disease. Design We studied the end-stage calcific aortic valves from male versus female patients to reveal the sex-dependent pathology differences and molecular changes associated with requiring valve replacement. Methods Aortic valves from 39 patients with rheumatic heart disease (19 males and 20 females) were collected at the time of aortic valve replacement for comparative pathology, immunohistochemistry, and gene expression analyses. Clinical characteristics were also analyzed and compared between the two groups. Results Aortic valves from female patients exhibited increased expression of collagens, infiltration of monocytes/macrophages and neovascularization. Aortic valves from female patients also had increased expression of inflammatory genes involved in the NFKB pathway (phosphorylated NFKB p65 subunit, IL8, and NOS3) and Th1 cytokine genes (IFNA and IL12B). The severe valve pathology in female patients was correlated with a higher serum level of anti-streptolysin O antibodies. Conclusion Inflammation is more prominent in aortic valves of female patients with rheumatic heart disease. This sex difference may contribute to the severe valve pathology and worse outcome of female patients.
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Affiliation(s)
- Feng Xiao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.,Departments of Genetics, Pediatrics and Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Rui Zheng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Di Yang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kejiang Cao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shijiang Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bingruo Wu
- Departments of Genetics, Pediatrics and Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Yongfeng Shao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bin Zhou
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.,Departments of Genetics, Pediatrics and Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, United States of America
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46
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Zhang C, Chen Z, Meng X, Li M, Zhang L, Huang A. The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-α) in thoracic ossification of the ligamentum flavum. PLoS One 2017; 12:e0178986. [PMID: 28575129 PMCID: PMC5456390 DOI: 10.1371/journal.pone.0178986] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 05/22/2017] [Indexed: 12/31/2022] Open
Abstract
Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic bone formation in the ligamentum flavum and is considered to be a leading cause of thoracic spinal canal stenosis and myelopathy. However, the underlying etiology is not well understood. An iTRAQ proteomics was used to reveal the involvement of inflammation factors in TOLF. TNF-α is a pro-inflammatory cytokine implicated in the pathogenesis of many human diseases. Protein profiling analysis showed that the protein level of TNF-α increased in the ossified ligamentum flavum of TOLF, which was confirmed by western blot. The effects of TNF-α on primary ligamentum flavum cells was examined. Cell proliferation assay demonstrated that primary cells from the ossified ligamentum flavum of TOLF grew faster than the control. Flow cytometry assay indicated that the proportions of cells in S phase of cell cycle of primary cells increased after TNF-α stimulation. To address the effect of TNF-α on gene expression, primary cells were derived from ligamentum flavum of TOLF patients. Culture cells were stimulated by TNF-α. RNA was isolated and analyzed by quantitative RT-PCR. G1/S-specific proteins cyclin D1 and c-Myc were upregulated after TNF-α stimulation. On the other hand, osteoblast differentiation related genes such as Bmp2 and Osterix (Osx) were upregulated in the presence of TNF-α. TNF-α activated Osx expression in a dose-dependent manner. Interestingly, a specific mitogen-activated protein kinase ERK inhibitor U0126, but not JNK kinase inhibitor SP600125, abrogated TNF-α activation of Osx expression. This suggests that TNF-α activates Osx expression through the mitogen-activated protein kinase ERK pathway. Taken together, we provide the evidence to support that TNF-α involves in TOLF probably through regulating cell proliferation via cyclin D1 and c-Myc, and promoting osteoblast differentiation via Osx.
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Affiliation(s)
- Chi Zhang
- Department of Orthopedics, Peking University International Hospital, Beijing, China
- Central Laboratory, Peking University International Hospital, Beijing, China
- Bone Research Laboratory, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
- * E-mail: (CZ); (ZC)
| | - Zhongqiang Chen
- Department of Orthopedics, Peking University Third Hospital, Haidian District, Beijing, China
- * E-mail: (CZ); (ZC)
| | - Xiangyu Meng
- Central Laboratory, Peking University International Hospital, Beijing, China
| | - Mengtao Li
- Central Laboratory, Peking University International Hospital, Beijing, China
| | - Li Zhang
- Department of Research, Daobio Inc., Dallas, Texas, United States of America
| | - Ann Huang
- Department of Research, Daobio Inc., Dallas, Texas, United States of America
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Abstract
PURPOSE OF REVIEW The mechanisms involved in the TNF-mediated deregulated bone remodeling are little appreciated. This review will discuss and summarize the impact of TNF, Notch, and RBP-J signaling on bone remodeling. RECENT FINDINGS The integrity of the adult skeleton undergoes constant and dynamic remodeling throughout life to maintain a proper bone homeostasis, which is achieved by the essential tight control of coupling between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. The studies in this field include not only the differentiation and function of osteoblasts and osteoclasts, but also the mechanisms that simultaneously control both cell types during bone remodeling. Chronic inflammation is one of the most evident and common pathological settings that often leads to deregulated bone remodeling. The resounding success of TNF blockade therapy has demonstrated a key role for TNF in inflammation and the pathogenesis of inflammatory bone resorption associated with diseases such as rheumatoid arthritis and periodontitis. Recent studies have highlighted the function of Notch and RBP-J signaling in both physiological and TNF-mediated inflammatory bone remodeling.
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Affiliation(s)
- Baohong Zhao
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA.
- Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
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Najar M, Krayem M, Meuleman N, Bron D, Lagneaux L. Mesenchymal Stromal Cells and Toll-Like Receptor Priming: A Critical Review. Immune Netw 2017; 17:89-102. [PMID: 28458620 PMCID: PMC5407987 DOI: 10.4110/in.2017.17.2.89] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/24/2017] [Accepted: 02/25/2017] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal Stromal Cells (MSCs) are potential cellular candidates for several immunotherapy purposes. Their multilineage potential and immunomodulatory properties make them interesting tools for the treatment of various immunological diseases. However, depending on the local microenvironment, diverse biological functions of MSCs can be modulated. Indeed, during infections such as obtained following TLR-agonist engagement (called as TLR priming), the phenotype, multilineage potential, hematopoietic support and immunomodulatory capacity of MSCs can present critical changes, which could further affect their therapeutic potential. Thus, for appropriate clinical application of MSCs, it is important to well know and understand these effects in particular during infectious episodes and to find the suitable experimental settings to study that. Pre-stimulation of MSCs with a specific TLR ligand may serve as an effective priming step to modulate one of its function to achieve a desired therapeutic issue.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Belgium
| | - Mohammad Krayem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels 1000, Belgium
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Belgium
| | - Dominique Bron
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Belgium
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Rohban MH, Singh S, Wu X, Berthet JB, Bray MA, Shrestha Y, Varelas X, Boehm JS, Carpenter AE. Systematic morphological profiling of human gene and allele function via Cell Painting. eLife 2017; 6. [PMID: 28315521 PMCID: PMC5386591 DOI: 10.7554/elife.24060] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 03/14/2017] [Indexed: 12/21/2022] Open
Abstract
We hypothesized that human genes and disease-associated alleles might be systematically functionally annotated using morphological profiling of cDNA constructs, via a microscopy-based Cell Painting assay. Indeed, 50% of the 220 tested genes yielded detectable morphological profiles, which grouped into biologically meaningful gene clusters consistent with known functional annotation (e.g., the RAS-RAF-MEK-ERK cascade). We used novel subpopulation-based visualization methods to interpret the morphological changes for specific clusters. This unbiased morphologic map of gene function revealed TRAF2/c-REL negative regulation of YAP1/WWTR1-responsive pathways. We confirmed this discovery of functional connectivity between the NF-κB pathway and Hippo pathway effectors at the transcriptional level, thereby expanding knowledge of these two signaling pathways that critically regulate tumor initiation and progression. We make the images and raw data publicly available, providing an initial morphological map of major biological pathways for future study. DOI:http://dx.doi.org/10.7554/eLife.24060.001 Many human diseases are caused by particular changes, called mutations, in patients’ DNA. A genome is the complete DNA set of an organism, which contains all the information to build the body and keep it working. This information is stored as a code made up of four chemicals called bases. Humans have about 30,000 genes built from DNA, which contain specific sequences of bases. Genome sequencing can determine the exact order of these bases, and has revealed a long list of mutations in genes that could cause particular diseases. However, over 30% of genes in the human body do not have a known role. Genes can serve multiple roles, some of which are not yet discovered, and even when a gene’s purpose is known, the impact of each particular mutation in a given gene is largely uncatalogued. Therefore, new methods need to be developed to identify the biological roles of both normal and abnormal gene sequences. For hundreds of years, biologists have used microscopy to study how living cells work. Rohban et al. have now asked whether modern software that extracts data from microscopy images could create a fingerprint-like profile of a cell that would reflect how its genes affect its role and appearance. While some genes do not necessarily carry a code with instructions of what a cell should look like, they can indirectly modify the structure of the cell. The resulting changes in the shape of the cell can then be captured in images. The idea was that two cells with matching profiles would indicate that their combinations of genes had matching biological roles too. Rohban et al. tested their approach with human cells grown in the laboratory. In each sample of cells, they ‘turned on’ one of a few hundred relatively well-known human genes, some of which were known to have similar roles. The cells were then stained via a technique called ‘Cell Painting’ to reveal eight specific components of each cell, including its DNA and its surface membrane. The stained cells were imaged under a microscope and the resulting microscopy images analyzed to create a profile of each type of cell. Rohban et al. confirmed that turning on genes known to perform similar biological roles lead to similar-looking cells. The analysis also revealed a previously unknown interaction between two major pathways in the cell that control how cancer starts and develops. In the future, this approach could predict the biological roles of less-understood genes by looking for profiles that match those of well-known genes. Applying this strategy to every human gene, and mutations in genes that are linked to diseases, could help to answer many mysteries about how genes build the human body and keep it working. DOI:http://dx.doi.org/10.7554/eLife.24060.002
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Affiliation(s)
| | - Shantanu Singh
- Broad Institute of MIT and Harvard, Cambridge, United States
| | - Xiaoyun Wu
- Broad Institute of MIT and Harvard, Cambridge, United States
| | - Julia B Berthet
- Department of Biochemistry, Boston University School of Medicine, Boston, United States
| | | | | | - Xaralabos Varelas
- Department of Biochemistry, Boston University School of Medicine, Boston, United States
| | - Jesse S Boehm
- Broad Institute of MIT and Harvard, Cambridge, United States
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Differential long noncoding RNA/mRNA expression profiling and functional network analysis during osteogenic differentiation of human bone marrow mesenchymal stem cells. Stem Cell Res Ther 2017; 8:30. [PMID: 28173844 PMCID: PMC5297123 DOI: 10.1186/s13287-017-0485-6] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/22/2016] [Accepted: 01/20/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are the most promising cell types for bone regeneration and repair due to their osteogenic potential. MSC differentiation is precisely regulated and orchestrated by the mechanical and molecular signals from the extracellular environment, involving complex pathways regulated at both the transcriptional and post-transcriptional levels. However, the potential role of long noncoding RNA (lncRNA) in the osteogenic differentiation of human MSCs remains largely unclear. METHODS Here, we undertook the survey of differential coding and noncoding transcript expression profiling and functional network analysis during osteogenic differentiation of human bone marrow mesenchymal stem cells (BMSCs) using human whole transcriptome microarray. The key pathways, mRNAs, and lncRNAs controlling osteogenic differentiation of BMSCs were identified by further bioinformatic analysis. The role of lncRNA in the osteogenic differentiation of MSCs was verified by lncRNA overexpression or knockdown methods. RESULTS A total of 1269 coding transcripts with 648 genes significantly upregulated and 621 genes downregulated, and 1408 lncRNAs with 785 lncRNAs significantly upregulated and 623 lncRNAs downregulated were detected along with osteogenic differentiation. Bioinformatic analysis identified that several pathways may be associated with osteogenic differentiation potentials of BMSCs, such as the MAPK signaling pathway, the Jak-STAT signaling pathway, the Toll-like receptor signaling pathway, and the TGF-beta signaling pathway, etc. Bioinformatic analysis also revealed 13 core regulatory genes including seven mRNAs (GPX3, TLR2, BDKRB1, FBXO5, BRCA1, MAP3K8, and SCARB1), and six lncRNAs (XR_111050, NR_024031, FR374455, FR401275, FR406817, and FR148647). Based on the analysis, we identified one lncRNA, XR_111050, that could enhance the osteogenic differentiation potentials of MSCs. CONCLUSIONS The potential regulatory mechanisms were identified using bioinformatic analyses. We further predicted the interactions of differentially expressed coding and noncoding genes, and identified core regulatory factors by co-expression networks during osteogenic differentiation of BMSCs. Our results could lead to a better understanding of the molecular mechanisms of genes and lncRNAs, and their cooperation underlying MSC osteogenic differentiation and bone formation. We identified that one lncRNA, XR_111050, could be a potential target for bone tissue engineering.
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