|
1
|
Jiang S, Zhang X, Chen F, Zhao Z, Zhang C, Sun Y. Ketone body 3-hydroxybutyrate mitigates apoptosis and enhances osteogenesis in bone organoid construction via the cAMP/PKA/CREB signaling pathway. FASEB J 2025; 39:e70510. [PMID: 40277379 DOI: 10.1096/fj.202402974r] [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: 11/25/2024] [Revised: 01/27/2025] [Accepted: 03/25/2025] [Indexed: 04/26/2025]
Abstract
Bone organoids offer potential for bone regeneration and in vitro organ models. Current limitations in bone organoid culture systems include low efficiency in construction and functionality, as well as increased apoptosis in prolonged cultures of larger sizes. The ketone body 3-hydroxybutyrate (3HB), synthesized in the liver, addresses these challenges effectively. Our findings suggest that 3HB increases intracellular calcium ion (Ca2+) levels in human bone marrow-derived mesenchymal stem cells (hBMSCs) by activating the hydroxycarboxylic acid receptor 2 (HCAR2). This activation initiates the cAMP/PKA/CREB pathway, which elevates the expression of anti-apoptotic genes such as myeloid cell leukemia 1 (MCL1) and B cell lymphoma 2-related protein A1 (BCL2A1), thereby reducing apoptosis. Furthermore, this pathway boosts the expression of osteogenic proteins, including Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2), facilitating osteogenesis in bone organoids. Consequently, 3HB may enhance the construction of bone organoids that are more mature, larger, and have longer viability.
Collapse
Affiliation(s)
- Songlun Jiang
- Center of Digital Dentistry, Peking University School of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & NHC Key Laboratory of Digital Stomatology & Beijing Key Laboratory of Digital Stomatology & Key Laboratory of Digital Stomatology, Chinese Academy of Medical Sciences, Beijing, China
| | - Xu Zhang
- Center of Digital Dentistry, Peking University School of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & NHC Key Laboratory of Digital Stomatology & Beijing Key Laboratory of Digital Stomatology & Key Laboratory of Digital Stomatology, Chinese Academy of Medical Sciences, Beijing, China
| | - Fanfan Chen
- Center of Digital Dentistry, Peking University School of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & NHC Key Laboratory of Digital Stomatology & Beijing Key Laboratory of Digital Stomatology & Key Laboratory of Digital Stomatology, Chinese Academy of Medical Sciences, Beijing, China
| | - Zifan Zhao
- Center of Digital Dentistry, Peking University School of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & NHC Key Laboratory of Digital Stomatology & Beijing Key Laboratory of Digital Stomatology & Key Laboratory of Digital Stomatology, Chinese Academy of Medical Sciences, Beijing, China
| | - Chenglong Zhang
- Center of Digital Dentistry, Peking University School of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & NHC Key Laboratory of Digital Stomatology & Beijing Key Laboratory of Digital Stomatology & Key Laboratory of Digital Stomatology, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuchun Sun
- Center of Digital Dentistry, Peking University School of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & NHC Key Laboratory of Digital Stomatology & Beijing Key Laboratory of Digital Stomatology & Key Laboratory of Digital Stomatology, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
2
|
Ning Q, Li M, Liao Z, Chen E, Liu H, Liang Y, Chen Y, Li Y, Huang L. LncRNA MRF targeting FSHR inhibits the osteogenic differentiation of BMSCs and bone defect repair through the regulation of the cAMP-PKA-CREB signaling pathway. Stem Cell Res Ther 2025; 16:200. [PMID: 40264197 PMCID: PMC12016372 DOI: 10.1186/s13287-025-04291-9] [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: 07/24/2024] [Accepted: 03/24/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs), known for their ability to differentiate into osteoblasts, play a pivotal role in bone metabolism. In our previous investigations, we identified a novel long non-coding RNA (lncRNA) named MCP1 Regulatory Factor (MRF), which exhibits significant involvement in immune regulation of BMSCs. Moreover, we observed noticeable expression changes of MRF during the osteogenic differentiation of BMSCs. However, the exact role and underlying mechanism of MRF in the osteogenic differentiation of BMSCs remain elusive. METHODS QRT-PCR analysis was employed to assess the expression levels of MRF. RNA interference and overexpression plasmids were utilized to modulate MRF expression, allowing for the observation of changes in the osteogenic differentiation capacity of BMSCs. Downstream pathways involved in the MRF-mediated regulation of BMSCs' osteogenic differentiation were predicted using transcriptome sequencing. The functionality of MRF in vivo was validated through a mouse tibial drilling defect model. RESULTS In patients with osteoporosis, there is a notable increase in the expression of MRF within BMSCs. During the osteogenic differentiation of BMSCs, the MRF expression progressively decreases. The knockdown of MRF significantly enhances the osteogenic differentiation of BMSCs, promoting an increased expression of bone-related proteins such as RUNX2, ALP, and COL1A1. Transcriptome sequencing and western blot indicated that cAMP/PKA/CREB signaling pathway was significantly activated after lncRNA-MRF knockdown. Moreover, in the mouse tibial drilling defect model, MRF knockdown significantly promotes ossification in vivo. CONCLUSIONS MRF modulates the cAMP/PKA/CREB signaling pathway via the follicle stimulating hormone receptor (FSHR), thereby influencing the ossification differentiation of BMSCs. Our research suggests that MRF may serve as a potential target for bone-related disorders.
Collapse
Affiliation(s)
- Qing Ning
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Ming Li
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Zhuangyao Liao
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Enming Chen
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Huatao Liu
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Yuwei Liang
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Yuanquan Chen
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Yuxi Li
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
| | - Lin Huang
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
| |
Collapse
|
|
3
|
Wang Q, Yang Y, Yuan X, Luo F, Ling Y, Chen C, Huang Y, Huang R, Ma W, Yao X. Jinwu Jiangu Capsule alleviates rheumatoid arthritis symptoms by regulating the ADCY10 and cAMP/RANKL pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119099. [PMID: 39542189 DOI: 10.1016/j.jep.2024.119099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 11/08/2024] [Accepted: 11/11/2024] [Indexed: 11/17/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects joints and damages other tissues, including the heart, kidneys, lungs, digestive system, eyes, skin and nervous system. Jinwu Jiangu Capsule (JWJG) is effective in tonifying kidneys, activating blood circulation, and dispelling wind and dampness. Meanwhile, it produces favorable clinical results in relieving joint pain and reducing inflammation. However, precise therapeutic effect and mechanisms of JWJG on RA remain unclear. AIM OF THE STUDY The traditional Chinese medicine JWJG exhibits certain properties in anti-inflammation and pain relief for RA treatment. This study aimed to investigate the efficacy of JWJG and elucidate its underlying mechanisms in RA treatment. MATERIALS AND METHODS A collagen-induced arthritis (CIA) rat model was administered JWJG orally at varying doses for 28 days, alongside control and positive control groups treated with saline and leflunomide, respectively. Indicators including joint swelling, bone loss, histopathological changes, Th17/Treg lymphocyte differentiation, and inflammatory factor expression were assessed. RNA sequencing of synovial tissues identified JWJG-influenced genes and pathways. RASFs treated with ADCY10 lentivirus, PKA agonist, or AR plasmid underwent additional JWJG-containing serum or β-sitosterol treatment to monitor ADCY10, RANKL, and cAMP pathway alterations. RESULTS JWJG administration significantly reduced joint swelling, bone loss, and inflammation, balanced Th17/Treg, and suppressed TNF-α, IL-1β, IL-6, and RANKL levels. In RASFs, JWJG downregulated ADCY10, cAMP, and phospho-PKA/CREB, thereby inhibiting osteoclast differentiation. Meanwhile, β-sitosterol decreased AR levels, which suppressed ADCY10 and RANKL expression. JWJG treatment could directly/indirectly inhibit ADCY10 reduced cAMP/RANKL, inflammation, and osteoclastogenesis, enhancing RA symptomatology comparable to leflunomide. It demonstrated superior regulation of Th17/Treg ratios and cytokine suppression, with potential to substantially improve RA patients' quality of life. CONCLUSIONS JWJG inhibited ADCY10, decreased cAMP/RANKL, and impeded inflammation and osteoclastogenesis, with a notable improvement in RA symptoms comparable to leflunomide. It can be introduced as a potential new therapeutic strategy for preventing or even reversing bone damage and improving the quality of life for RA patients.
Collapse
Affiliation(s)
- Qiuyi Wang
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China
| | - Yuzheng Yang
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China
| | - Xuemei Yuan
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China
| | - Feng Luo
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China
| | - Yi Ling
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China
| | - Changming Chen
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China
| | - Ying Huang
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China
| | - Runyue Huang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guiyang, Guizhou Province, 550001, China.
| | - Wukai Ma
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China.
| | - Xueming Yao
- Department of Rheumatology Immunology, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, 550001, China; Department of Liupanshui Hospital of Traditional Chinese Medicine, Liupanshui, Guizhou Province, 553000, China.
| |
Collapse
|
|
4
|
Mouzoura P, Marazioti A, Gkartziou F, Metsiou DN, Antimisiaris SG. Potential of Liposomal FTY720 for Bone Regeneration: Proliferative, Osteoinductive, Chemoattractive, and Angiogenic Properties Compared to Free Bioactive Lipid. Int J Nanomedicine 2025; 20:239-265. [PMID: 39802384 PMCID: PMC11724662 DOI: 10.2147/ijn.s494512] [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: 10/09/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025] Open
Abstract
Introduction FTY720 bioactive lipid has proliferative, osteoinductive, chemo attractive, and angiogenic properties, being thus a potential exogenous administered agent for promotion of bone regeneration. Herein we developed FTY720-loaded liposomes as a potential delivery system that could retain and prolong the bioactivity of the bioactive lipid and at the same time reduce its cytotoxicity (at high doses). Methods FTY720 liposomes were prepared by thin-lipid hydration and microfluidic flow focusing, and evaluated for their ability to induce proliferation, osteoinduction, and chemoattraction in three cell types: MC3T3-E1 pre-osteoblast cells, L929 fibroblast cells, and ATDC5 chondrogenic cells. The angiogenic activity of free and liposomal FTY720 was investigated using a chick chorioallantoic membrane assay. NBD-FTY720 cellular uptake was quantitated using flow cytometry and morphologically assessed by confocal microscopy. Implicated cellular signaling mechanisms were investigated by quantifying phosphorylated MAPK and CREB proteins. Results FTY720 liposomes (~80-110 nm) with low polydispersity and ~100% loading were prepared using both methods. FTY720 demonstrated the ability to increase cell proliferation at 10-300nM doses but was cytotoxic at doses>400nM while the corresponding liposomal-FTY720 doses were non-cytotoxic, proving its reduced toxicity. In several cases (cells and doses), FTY720 liposomes demonstrated increased osteogenic differentiation of cells, proliferation, and migration compared to free FTY720, whereas both FTY720 forms demonstrated substantial angiogenic activity. Liposomal FTY720 cellular uptake was substantially higher than that of free FTY720 in some cases, a fact that may be connected to its higher bioactivity. Increased phosphorylated MAPK and CREB protein concentrations provided information about the potential cellular signaling mechanisms involved in FTY720-induced osteogenesis. Discussion The current results confirm the high potential of FTY720 bioactive lipid, especially in its liposomal form, that demonstrated substantial reduction of cytotoxicity and prolonged preservation of the lipids bioactivity (compared to the free lipid), for accelerated treatment of bone defects. Interestingly, the current studies prove the potential of FTY720, especially in its liposomal form, to promote reprogramming of L929 fibroblasts into osteoblasts, a novel finding deserving future exploitation.
Collapse
Affiliation(s)
- Panagiota Mouzoura
- Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion, 26504, Greece
| | - Antonia Marazioti
- Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion, 26504, Greece
- Laboratory of Basic Sciences, Department of Physiotherapy, University of the Peloponnese, Sparti, 23100, Greece
| | - Foteini Gkartziou
- Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion, 26504, Greece
| | - Despoina-Nektaria Metsiou
- Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion, 26504, Greece
| | - Sophia G Antimisiaris
- Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion, 26504, Greece
- FORTH/ICE‑ΗΤ, Institute of Chemical Engineering Sciences, Platani, 26504, Greece
| |
Collapse
|
|
5
|
Standing D, Dandawate P, Gunewardena S, Covarrubias-Zambrano O, Roby KF, Khabele D, Jewell A, Tawfik O, Bossmann SH, Godwin AK, Weir SJ, Jensen RA, Anant S. Selective targeting of IRAK1 attenuates low molecular weight hyaluronic acid-induced stemness and non-canonical STAT3 activation in epithelial ovarian cancer. Cell Death Dis 2024; 15:362. [PMID: 38796478 PMCID: PMC11127949 DOI: 10.1038/s41419-024-06717-3] [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: 11/29/2023] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/28/2024]
Abstract
Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with ~25% surviving beyond 5 years. Evidence suggests that cancer stem cells contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. Moreover, low molecular weight hyaluronic acid, which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC.
Collapse
Affiliation(s)
- David Standing
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sumedha Gunewardena
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
| | | | - Katherine F Roby
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Dineo Khabele
- Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, USA
| | - Andrea Jewell
- Department of Gynecologic Oncology, University of Kansas Medical Center, Kansas City, KS, USA
| | | | - Stefan H Bossmann
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Andrew K Godwin
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
- Kansas Institute for Precision Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Scott J Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
- Department of Pharmacology and Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
- Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS, USA
| | - Roy A Jensen
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
| |
Collapse
|
|
6
|
Wang MC, Yu WL, Ding YC, Huang JJ, Lin CY, Tseng WJ. Persistent Mesodermal Differentiation Capability of Bone Marrow MSCs Isolated from Aging Patients with Low-Energy Traumatic Hip Fracture and Osteoporosis: A Clinical Evidence. Int J Mol Sci 2024; 25:5273. [PMID: 38791313 PMCID: PMC11120803 DOI: 10.3390/ijms25105273] [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: 02/28/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
A low-energy hit, such as a slight fall from a bed, results in a bone fracture, especially in the hip, which is a life-threatening risk for the older adult and a heavy burden for the social economy. Patients with low-energy traumatic bone fractures usually suffer a higher level of bony catabolism accompanied by osteoporosis. Bone marrow-derived stem cells (BMSCs) are critical in osteogenesis, leading to metabolic homeostasis in the healthy bony microenvironment. However, whether the BMSCs derived from the patients who suffered osteoporosis and low-energy traumatic hip fractures preserve a sustained mesodermal differentiation capability, especially in osteogenesis, is yet to be explored in a clinical setting. Therefore, we aimed to collect BMSCs from clinical hip fracture patients with osteoporosis, followed by osteogenic differentiation comparison with BMSCs from healthy young donors. The CD markers identification, cytokines examination, and adipogenic differentiation were also evaluated. The data reveal that BMSCs collected from elderly osteoporotic patients secreted approximately 122.8 pg/mL interleukin 6 (IL-6) and 180.6 pg/mL vascular endothelial growth factor (VEGF), but no PDGF-BB, IL-1b, TGF-b1, IGF-1, or TNF-α secretion. The CD markers and osteogenic and adipogenic differentiation capability in BMSCs from these elderly osteoporotic patients and healthy young donors are equivalent and compliant with the standards defined by the International Society of Cell Therapy (ISCT). Collectively, our data suggest that the elderly osteoporotic patients-derived BMSCs hold equivalent differentiation and proliferation capability and intact surface markers identical to BMSCs collected from healthy youth and are available for clinical cell therapy.
Collapse
Affiliation(s)
- Mei-Chih Wang
- Biomedical Technology & Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31057, Taiwan; (M.-C.W.); (W.-L.Y.); (Y.-C.D.); (J.-J.H.)
- Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu 300102, Taiwan
| | - Wei-Lin Yu
- Biomedical Technology & Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31057, Taiwan; (M.-C.W.); (W.-L.Y.); (Y.-C.D.); (J.-J.H.)
| | - Yun-Chiao Ding
- Biomedical Technology & Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31057, Taiwan; (M.-C.W.); (W.-L.Y.); (Y.-C.D.); (J.-J.H.)
| | - Jun-Jae Huang
- Biomedical Technology & Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31057, Taiwan; (M.-C.W.); (W.-L.Y.); (Y.-C.D.); (J.-J.H.)
| | - Chin-Yu Lin
- Department of Biomedical Sciences and Engineering, Tzu Chi University, Hualien 97004, Taiwan
- Institute of New Drug Development, College of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Wo-Jan Tseng
- Department of Orthopedic Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 300195, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
| |
Collapse
|
|
7
|
Li K, Huo Q, Minami K, Tamari K, Ogawa K, Na S, Fishel ML, Li BY, Yokota H. Exploring the Tumor-Suppressing Potential of PSCA in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:4917. [PMID: 37894284 PMCID: PMC10605218 DOI: 10.3390/cancers15204917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/03/2023] [Accepted: 10/07/2023] [Indexed: 10/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates. We explored an innovative therapeutic approach by leveraging prognostic oncogenic markers. Instead of inhibiting these marker genes, we harnessed their tumor-modifying potential in the extracellular domain. Surprisingly, many of the proteins highly expressed in PDAC, which is linked to poor survival, exhibited tumor-suppressing qualities in the extracellular environment. For instance, prostate stem cell antigens (PSCA), associated with reduced survival, acted as tumor suppressors when introduced extracellularly. We performed in vitro assays to assess the proliferation and migration and evaluated the tumor-modifying capacity of extracellular factors from peripheral blood mononuclear cells (PBMCs) in PDAC tissues. Molecular docking analysis, immunoprecipitation, Western blotting, and RNA interference were employed to study the regulatory mechanism. Extracellular PSCA recombinant protein notably curtailed the viability, motility, and transwell invasion of PDAC cells. Its anti-PDAC effects were partially mediated by Mesothelin (MSLN), another highly expressed tumor-associated antigen in PDAC. The anti-tumor effects of extracellular PSCA complemented those of chemotherapeutic agents like Irinotecan, 5-Fluorouracil, and Oxaliplatin. PSCA expression increased in a conditioned medium derived from PBMCs and T lymphocytes. This study unveils the paradoxical anti-PDAC potential of PSCA, hinting at the dual roles of oncoproteins like PSCA in PDAC suppression.
Collapse
Affiliation(s)
- Kexin Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China; (K.L.); (Q.H.)
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA;
| | - Qingji Huo
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China; (K.L.); (Q.H.)
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA;
| | - Kazumasa Minami
- Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Suita 565-0871, Osaka, Japan; (K.M.); (K.T.); (K.O.)
| | - Keisuke Tamari
- Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Suita 565-0871, Osaka, Japan; (K.M.); (K.T.); (K.O.)
| | - Kazuhiko Ogawa
- Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Suita 565-0871, Osaka, Japan; (K.M.); (K.T.); (K.O.)
| | - Sungsoo Na
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA;
| | - Melissa L. Fishel
- Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA
| | - Bai-Yan Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China; (K.L.); (Q.H.)
| | - Hiroki Yokota
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA;
- Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| |
Collapse
|
|
8
|
Song X, Bai Y, Yuan R, Zhu H, Lan X, Qu L. InDel and CNV within the AKAP13 Gene Revealing Strong Associations with Growth Traits in Goat. Animals (Basel) 2023; 13:2746. [PMID: 37685010 PMCID: PMC10487263 DOI: 10.3390/ani13172746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/24/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
A-kinase-anchoring protein 13 (AKAP13) is a member of the AKAP protein family that has been found to be associated with bone formation. Thus, we investigated the AKAP13 gene as a potential candidate gene for molecular-marker-assisted selection (MAS) in breeding. Our aim was to explore genetic variations (InDel and CNV) within the AKAP13 gene of Shaanbei white cashmere (SBWC) goats and analyze their relationship with growth traits. Ultimately, we identified three InDel loci (16-bp deletion, 15-bp insertion, and 25-bp deletion) and three CNVs, and the 16-bp and 15-bp loci were significantly associated with goat body length (p < 0.05). Both the 16-bp deletion variant and the 15-bp insertion variant facilitated an increase in body length in goats. In addition to this, there was a certain superposition effect between 16-bp and 15-bp loci, although there was no linkage. Additionally, the CNV1 locus was significantly correlated with body height and body length of goats (p < 0.05), and CNV2 was significantly correlated with chest depth, chest circumference, and cannon circumference of goats (p < 0.05). Individuals with gain type showed excellent growth performance. In conclusion, the InDel and CNV loci that we have identified could possibly serve as effective molecular markers in goat breeding, which is very essential for improving efficiency and success of breeding. Moreover, our findings provide a new avenue for further research into the function of the AKAP13 gene.
Collapse
Affiliation(s)
- Xiaoyue Song
- Shaanxi Provincial Engineering and Technology Research Center of Cashmere Goats, Yulin University, Yulin 719000, China; (X.S.); (Y.B.); (R.Y.); (H.Z.)
- College of Life Sciences, Yulin University, Yulin 719000, China
| | - Yangyang Bai
- Shaanxi Provincial Engineering and Technology Research Center of Cashmere Goats, Yulin University, Yulin 719000, China; (X.S.); (Y.B.); (R.Y.); (H.Z.)
- College of Life Sciences, Yulin University, Yulin 719000, China
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Rongrong Yuan
- Shaanxi Provincial Engineering and Technology Research Center of Cashmere Goats, Yulin University, Yulin 719000, China; (X.S.); (Y.B.); (R.Y.); (H.Z.)
- College of Life Sciences, Yulin University, Yulin 719000, China
| | - Haijing Zhu
- Shaanxi Provincial Engineering and Technology Research Center of Cashmere Goats, Yulin University, Yulin 719000, China; (X.S.); (Y.B.); (R.Y.); (H.Z.)
- College of Life Sciences, Yulin University, Yulin 719000, China
| | - Xianyong Lan
- College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China
| | - Lei Qu
- Shaanxi Provincial Engineering and Technology Research Center of Cashmere Goats, Yulin University, Yulin 719000, China; (X.S.); (Y.B.); (R.Y.); (H.Z.)
- College of Life Sciences, Yulin University, Yulin 719000, China
| |
Collapse
|
|
9
|
Xie L, Feng E, Li S, Chai H, Chen J, Li L, Ge J. Comparisons of gene expression between peripheral blood mononuclear cells and bone tissue in osteoporosis. Medicine (Baltimore) 2023; 102:e33829. [PMID: 37335694 PMCID: PMC10194530 DOI: 10.1097/md.0000000000033829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 05/02/2023] [Indexed: 06/21/2023] Open
Abstract
Osteoporosis (OP) is one of the major public health problems in the world. However, the biomarkers between the peripheral blood mononuclear cells (PBMs) and bone tissue for prognosis of OP have not been well characterized. This study aimed to explore the similarities and differences of the gene expression profiles between the PBMs and bone tissue and identify potential genes, transcription factors (TFs) and hub proteins involved in OP. The patients were enrolled as an experimental group, and healthy subjects served as normal controls. Human whole-genome expression chips were used to analyze gene expression profiles from PBMs and bone tissue. And the differentially expressed genes (DEGs) were subsequently studied using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. The above DEGs were constructed into protein-protein interaction network. Finally, TF-DEGs regulation networks were constructed. Microarray analysis revealed that 226 DEGs were identified between OP and normal controls in the PBMs, while 2295 DEGs were identified in the bone tissue. And 13 common DEGs were obtained by comparing the 2 tissues. The Gene Ontology analysis indicated that DEGs in the PBMs were more involved in immune response, while DEGs in bone were more involved in renal response and urea transmembrane transport. And the Kyoto Encyclopedia of Genes and Genomes analysis indicated almost all of the pathways in the PBMs were overlapped with those in the bone tissue. Furthermore, protein-protein interaction network presented 6 hub proteins: PI3K1, APP, GNB5, FPR2, GNG13, and PLCG1. APP has been found to be associated with OP. Finally, 5 key TFs were identified by TF-DEGs regulation networks analysis (CREB1, RUNX1, STAT3, CREBBP, and GLI1) and were supposed to be associated with OP. This study enhanced our understanding of the pathogenesis of OP. PI3K1, GNB5, FPR2, GNG13, and PLCG1 might be the potential targets of OP.
Collapse
Affiliation(s)
- Lihua Xie
- Key Research Laboratory of Osteoporosis Syndrome Genomics, Fujian Academy of Chinese Medical Sciences, Fuzhou, China
| | - Eryou Feng
- Department of Arthrosis Surgery, Fuzhou Second Hospital, Fuzhou, China
| | - Shengqiang Li
- Key Research Laboratory of Osteoporosis Syndrome Genomics, Fujian Academy of Chinese Medical Sciences, Fuzhou, China
| | - Hao Chai
- Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Juan Chen
- Key Research Laboratory of Osteoporosis Syndrome Genomics, Fujian Academy of Chinese Medical Sciences, Fuzhou, China
| | - Li Li
- Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Jirong Ge
- Key Research Laboratory of Osteoporosis Syndrome Genomics, Fujian Academy of Chinese Medical Sciences, Fuzhou, China
| |
Collapse
|
|
10
|
Li K, Huo Q, Dimmitt NH, Qu G, Bao J, Pandya PH, Saadatzadeh MR, Bijangi-Vishehsaraei K, Kacena MA, Pollok KE, Lin CC, Li BY, Yokota H. Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins. eLife 2023; 12:e83768. [PMID: 36943734 PMCID: PMC10030111 DOI: 10.7554/elife.83768] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 03/01/2023] [Indexed: 03/23/2023] Open
Abstract
Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and OS-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with cisplatin. CM was enriched with proteins such as calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of CALR transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein, a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.
Collapse
Affiliation(s)
- Kexin Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical UniversityHarbinChina
- Department of Biomedical Engineering, Indiana University Purdue University IndianapolisIndianapolisUnited States
| | - Qingji Huo
- Department of Pharmacology, School of Pharmacy, Harbin Medical UniversityHarbinChina
- Department of Biomedical Engineering, Indiana University Purdue University IndianapolisIndianapolisUnited States
| | - Nathan H Dimmitt
- Department of Biomedical Engineering, Indiana University Purdue University IndianapolisIndianapolisUnited States
| | - Guofan Qu
- Department of Orthopedic Surgery, Harbin Medical University Cancer HospitalHarbinChina
| | - Junjie Bao
- Department of Orthopedic Surgery, Harbin Medical University Cancer HospitalHarbinChina
| | - Pankita H Pandya
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of MedicineIndianapolisUnited States
- Department of Pediatrics, Indiana University School of MedicineIndianapolisUnited States
| | - M Reza Saadatzadeh
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of MedicineIndianapolisUnited States
- Department of Pediatrics, Indiana University School of MedicineIndianapolisUnited States
| | | | - Melissa A Kacena
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of MedicineIndianapolisUnited States
- Department of Orthopaedic Surgery, Indiana University School of MedicineIndianapolisUnited States
- Indiana Center for Musculoskeletal Health, Indiana University School of MedicineIndianapolisUnited States
| | - Karen E Pollok
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of MedicineIndianapolisUnited States
- Department of Pediatrics, Indiana University School of MedicineIndianapolisUnited States
| | - Chien-Chi Lin
- Department of Biomedical Engineering, Indiana University Purdue University IndianapolisIndianapolisUnited States
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of MedicineIndianapolisUnited States
| | - Bai-Yan Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical UniversityHarbinChina
| | - Hiroki Yokota
- Department of Biomedical Engineering, Indiana University Purdue University IndianapolisIndianapolisUnited States
- Indiana University Simon Comprehensive Cancer Center, Indiana University School of MedicineIndianapolisUnited States
- Indiana Center for Musculoskeletal Health, Indiana University School of MedicineIndianapolisUnited States
| |
Collapse
|
|
11
|
Purine metabolites promote ectopic new bone formation in ankylosing spondylitis. Int Immunopharmacol 2023; 116:109810. [PMID: 36774858 DOI: 10.1016/j.intimp.2023.109810] [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: 11/04/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 02/12/2023]
Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that mainly affects the axial skeleton, whose typical features are inflammatory back pain, bone structural damage and pathological new bone formation. The pathology of ectopic new bone formation is still little known. In this study, we found increased purine metabolites in plasma of patients with AS. Similarly, metabolome analysis indicated increased purine metabolites in both serum of CD4-Cre; Ptpn11fl/fl and SHP2-deficient chondrocytes. SHP2-deficient chondrocytes promoted the growth of wild type chondrocytes and differentiation of osteoblasts in CD4-Cre; Ptpn11fl/fl mice, which spontaneously developed AS-like bone disease. Purine metabolites, along with PTHrP derived from SHP2-deficient chondrocytes, accelerated the growth of chondrocytes and ectopic new bone formation through PKA/CREB signaling. Moreover, Suramin, a purinergic receptor antagonist, suppressed pathological new bone formation in AS-like bone disease. Overall, these results highlight the potential role of targeting purinergic signaling in retarding ectopic new bone formation in AS.
Collapse
|
|
12
|
Bakhshandeh B, Ranjbar N, Abbasi A, Amiri E, Abedi A, Mehrabi M, Dehghani Z, Pennisi CP. Recent progress in the manipulation of biochemical and biophysical cues for engineering functional tissues. Bioeng Transl Med 2023; 8:e10383. [PMID: 36925674 PMCID: PMC10013802 DOI: 10.1002/btm2.10383] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/28/2022] [Accepted: 07/16/2022] [Indexed: 11/11/2022] Open
Abstract
Tissue engineering (TE) is currently considered a cutting-edge discipline that offers the potential for developing treatments for health conditions that negatively affect the quality of life. This interdisciplinary field typically involves the combination of cells, scaffolds, and appropriate induction factors for the regeneration and repair of damaged tissue. Cell fate decisions, such as survival, proliferation, or differentiation, critically depend on various biochemical and biophysical factors provided by the extracellular environment during developmental, physiological, and pathological processes. Therefore, understanding the mechanisms of action of these factors is critical to accurately mimic the complex architecture of the extracellular environment of living tissues and improve the efficiency of TE approaches. In this review, we recapitulate the effects that biochemical and biophysical induction factors have on various aspects of cell fate. While the role of biochemical factors, such as growth factors, small molecules, extracellular matrix (ECM) components, and cytokines, has been extensively studied in the context of TE applications, it is only recently that we have begun to understand the effects of biophysical signals such as surface topography, mechanical, and electrical signals. These biophysical cues could provide a more robust set of stimuli to manipulate cell signaling pathways during the formation of the engineered tissue. Furthermore, the simultaneous application of different types of signals appears to elicit synergistic responses that are likely to improve functional outcomes, which could help translate results into successful clinical therapies in the future.
Collapse
Affiliation(s)
- Behnaz Bakhshandeh
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Nika Ranjbar
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Elahe Amiri
- Department of Life Science Engineering, Faculty of New Sciences and TechnologyUniversity of TehranTehranIran
| | - Ali Abedi
- Department of Life Science Engineering, Faculty of New Sciences and TechnologyUniversity of TehranTehranIran
| | - Mohammad‐Reza Mehrabi
- Department of Microbial Biotechnology, School of Biology, College of ScienceUniversity of TehranTehranIran
| | - Zahra Dehghani
- Department of Biotechnology, College of ScienceUniversity of TehranTehranIran
| | - Cristian Pablo Pennisi
- Regenerative Medicine Group, Department of Health Science and TechnologyAalborg UniversityAalborgDenmark
| |
Collapse
|
|
13
|
Li Q, Wang R, Zhang Z, Wang H, Lu X, Zhang J, Kong APS, Tian XY, Chan HF, Chung ACK, Cheng JCY, Jiang Q, Lee WYW. Sirt3 mediates the benefits of exercise on bone in aged mice. Cell Death Differ 2023; 30:152-167. [PMID: 36153410 PMCID: PMC9883264 DOI: 10.1038/s41418-022-01053-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 08/16/2022] [Accepted: 08/22/2022] [Indexed: 02/01/2023] Open
Abstract
Exercise in later life is important for bone health and delays the progression of osteoporotic bone loss. Osteocytes are the major bone cells responsible for transforming mechanical stimuli into cellular signals through their highly specialized lacunocanalicular networks (LCN). Osteocyte activity and LCN degenerate with aging, thus might impair the effectiveness of exercise on bone health; however, the underlying mechanism and clinical implications remain elusive. Herein, we showed that deletion of Sirt3 in osteocytes could impair the formation of osteocyte dendritic processes and inhibit bone gain in response to exercise in vivo. Mechanistic studies revealed that Sirt3 regulates E11/gp38 through the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway. Additionally, the Sirt3 activator honokiol enhanced the sensitivity of osteocytes to fluid shear stress in vitro, and intraperitoneal injection of honokiol reduced bone loss in aged mice in a dose-dependent manner. Collectively, Sirt3 in osteocytes regulates bone mass and mechanical responses through the regulation of E11/gp38. Therefore, targeting Sirt3 could be a novel therapeutic strategy to prevent age-related bone loss and augment the benefits of exercise on the senescent skeleton.
Collapse
Affiliation(s)
- Qiangqiang Li
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Rongliang Wang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhe Zhang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China
| | - Haixing Wang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaomin Lu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Jiajun Zhang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiao Yu Tian
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Hon-Fai Chan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Arthur Chi-Kong Chung
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Jack Chun-Yiu Cheng
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China
| | - Qing Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China.
| | - Wayne Yuk-Wai Lee
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
- SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, The Chinese University of Hong Kong, Hong Kong, China.
| |
Collapse
|
|
14
|
Awale G, Kan HM, Laurencin CT, Lo KWH. Molecular Mechanisms Underlying the Short-Term Intervention of Forskolin-Mediated Bone Regeneration. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2022. [DOI: 10.1007/s40883-022-00285-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
|
|
15
|
Deng L, Li X, Ren X, Lai S, Zhu Y, Li J, Huang H, Mu Y. A grooved porous hydroxyapatite scaffold induces osteogenic differentiation via regulation of PKA activity by upregulating miR-129-5p expression. J Periodontal Res 2022; 57:1238-1255. [PMID: 36222334 DOI: 10.1111/jre.13060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/15/2022] [Accepted: 09/27/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND AND OBJECTIVE Hydroxyapatite scaffolds with different morphologies have been widely used in bone tissue engineering. Moreover, microRNAs (miRNAs) have been proven to be extensively involved in regulating bone regeneration. We developed grooved porous hydroxyapatite (HAG) scaffolds with good osteogenic efficiency. However, little is known about the role of miRNAs in HAG scaffold-mediated promotion of bone regeneration. The objective of this study was to reveal the mechanism from the perspective of differential miRNA expression. METHODS Scanning electron microscopy (SEM) was used to perform the coculture of cells and scaffolds. The miRNA profiles were generated by a microarray assay. A synthetic miR-129-5p mimic and inhibitor were used for overexpression or inhibition. The expression of osteogenic marker mRNAs and proteins was detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence. An ALP activity kit and alizarin red staining (ARS) were used to measure ALP activity and mineral deposition formation. Cell migration ability was examined by wound healing and transwell assays. Protein kinase A (PKA) activity was measured by enzyme-linked immunosorbent assay (ELISA) after miR-129-5p transfection. Target genes were identified by a dual-luciferase reporter assay. H89 preculture evaluated the cross talk between miR-129-5p and PKA activity. Heterotopic implantation models, hematoxylin-eosin (HE), immunohistochemistry staining, and micro-CT were used to evaluate miR-129-5p osteogenesis in vivo. RESULTS miRNAs were differentially expressed during osteogenic differentiation induced by HAG in vitro and in vivo. miR-129-5p was the only highly expressed miRNA both in vitro and in vivo. miR-129-5p overexpression promoted osteoblast differentiation and cell migration, while its inhibition weakened the effect of HAG. Moreover, miR-129-5p activated PKA to regulate the phosphorylation of β-catenin and cAMP-response element binding protein (CREB) by inhibiting cAMP-dependent protein kinase inhibitor alpha (Pkia). H89 prevented the effects of miR-129-5p on osteogenic differentiation and cell migration. HE, immunohistochemistry staining and micro-CT results showed that miR-129-5p promoted in vivo osteogenesis of the HAG scaffold. CONCLUSION The HAG scaffold activates Pka by upregulating miR-129-5p and inhibiting Pkia, resulting in CREB-dependent transcriptional activation and accumulation of β-catenin and promoting osteogenic marker expression.
Collapse
Affiliation(s)
- Li Deng
- Stomatology Department, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.,Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, China
| | - Xinlun Li
- Stomatology Department, Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiaohua Ren
- Stomatology Department, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shuang Lai
- Stomatology Department, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yushu Zhu
- Stomatology Department, Sichuan Provincial People's Hospital, Chengdu, China
| | - Jing Li
- Stomatology Department, Sichuan Provincial People's Hospital, Chengdu, China
| | - Hao Huang
- Key Laboratory of Advanced Technologies of Materials (Ministry of Education), School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Yandong Mu
- Stomatology Department, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| |
Collapse
|
|
16
|
Suppression of osteosarcoma progression by engineered lymphocyte-derived proteomes. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
|
|
17
|
Ren N, Liang N, Dong M, Feng Z, Meng L, Sun C, Wang A, Yu X, Wang W, Xie J, Liu C, Liu H. Stem Cell Membrane-Encapsulated Zeolitic Imidazolate Framework-8: A Targeted Nano-Platform for Osteogenic Differentiation. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2202485. [PMID: 35633288 DOI: 10.1002/smll.202202485] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/12/2022] [Indexed: 06/15/2023]
Abstract
Mesenchymal stem cells (MSCs) have been recognized as one of the most promising pharmaceutical multipotent cells, and a key step for their wide application is to safely and efficiently regulate their activities. Various methods have been proposed to regulate the directional differentiation of MSCs during tissue regeneration, such as nanoparticles and metal ions. Herein, nanoscale zeolitic imidazolate framework-8 (ZIF-8), a Zn-based metal-organic framework, is modified to direct MSCs toward an osteoblast lineage. Specifically, ZIF-8 nanoparticles are encapsulated using stem cell membranes (SCMs) to mimic natural molecules and improve the biocompatibility and targeted ability toward MSCs. SCM/ZIF-8 nanoparticles adjust the sustained release of Zn2+ , and promote their specific internalization toward MSCs. The internalized SCM/ZIF-8 nanoparticles show excellent biocompatibility, and increase MSCs' osteogenic potentials. Moreover, RNA-sequencing results elucidate that the activated cyclic adenosine 3,5-monophosphate (cAMP)-PKA-CREB signaling pathway can be dominant in accelerating osteogenic differentiation. In vivo, SCM/ZIF-8 nanoparticles greatly promote the formation of new bone tissue in the femoral bone defect detected by 3D micro-CT, hematoxylin and eosin staining, and Masson staining after 4 weeks. Overall, the SCM-derived ZIF-8 nanostructures achieve the superior targeting ability, biocompatibility, and enhanced osteogenesis, providing a constructive design for tissue repair.
Collapse
Affiliation(s)
- Na Ren
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
| | - Na Liang
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
| | - Mengwei Dong
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
| | - Zhichao Feng
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
| | - Ling Meng
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
| | - Chunhui Sun
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
| | - Aizhu Wang
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
| | - Xin Yu
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
| | - Wenhan Wang
- State Key Laboratory of Crystal Materials, Shandong University, Jinan, 250100, P. R. China
| | - Juan Xie
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
- School of Physics and Engineering, Zhengzhou University, Zhengzhou, 450001, P. R. China
| | - Chao Liu
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, Institute of Stomatology, Shandong University, Jinan, 250012, P. R. China
| | - Hong Liu
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Institute for Advanced Interdisciplinary Research (iAIR), University of Jinan, Jinan, 250022, P. R. China
- State Key Laboratory of Crystal Materials, Shandong University, Jinan, 250100, P. R. China
| |
Collapse
|
|
18
|
Chen X, Xu Y, Li C, Lu X, Fu Y, Huang Q, Ma D, Ma J, Zhang T. Key Genes Identified in Nonsyndromic Microtia by the Analysis of Transcriptomics and Proteomics. ACS OMEGA 2022; 7:16917-16927. [PMID: 35647449 PMCID: PMC9134388 DOI: 10.1021/acsomega.1c07059] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/05/2022] [Indexed: 06/15/2023]
Abstract
As one of the common birth defects worldwide, nonsyndromic microtia is a complex disease that results from interactions between environmental and genetic factors. However, the underlying causes of nonsyndromic microtia are currently not well understood. The present study determined transcriptomic and proteomic profiles of auricular cartilage tissues in 10 patients with third-degree nonsyndromic microtia and five control subjects by RNA microarray and tandem mass tag-based quantitative proteomics technology. Relative mRNA and protein abundances were compared and evaluated for their function and putative involvement in nonsyndromic microtia. A total of 3971 differentially expressed genes and 256 differentially expressed proteins were identified. Bioinformatics analysis demonstrated that some of these genes and proteins showed potential associations with nonsyndromic microtia. Thirteen proteins with the same trend at the mRNA level obtained by the integrated analysis were validated by parallel reaction monitoring analysis. Several key genes, namely, LAMB2, COMP, APOA2, APOC2, APOC3, and A2M, were found to be dysregulated, which could contribute to nonsyndromic microtia. The present study is the first report on the transcriptomic and proteomic integrated analysis of nonsyndromic microtia using the same auricular cartilage sample. Additional studies are required to clarify the roles of potential key genes in nonsyndromic microtia.
Collapse
Affiliation(s)
- Xin Chen
- ENT
institute, Eye & ENT Hospital, Fudan
University, Shanghai 200031, China
| | - Yuexin Xu
- Key
Laboratory of Metabolism and Molecular Medicine, Ministry of Education,
Department of Biochemistry and Molecular Biology, School of Basic
Medical Sciences, Fudan University, Shanghai 200032, China
| | - Chenlong Li
- Department
of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Xinyu Lu
- ENT
institute, Eye & ENT Hospital, Fudan
University, Shanghai 200031, China
| | - Yaoyao Fu
- Department
of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Qingqing Huang
- Department
of Bioinformatics, Medical Laboratory of
Nantong Zhongke, Nantong, Jiangsu 226133, China
| | - Duan Ma
- Key
Laboratory of Metabolism and Molecular Medicine, Ministry of Education,
Department of Biochemistry and Molecular Biology, School of Basic
Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jing Ma
- ENT
institute, Eye & ENT Hospital, Fudan
University, Shanghai 200031, China
- Department
of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Tianyu Zhang
- ENT
institute, Eye & ENT Hospital, Fudan
University, Shanghai 200031, China
- Department
of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- NHC
Key Laboratory of Hearing Medicine, Fudan
University, Shanghai 200031, China
| |
Collapse
|
|
19
|
Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells. Cancers (Basel) 2021; 13:cancers13225593. [PMID: 34830748 PMCID: PMC8615769 DOI: 10.3390/cancers13225593] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/28/2021] [Accepted: 11/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Osteoclasts are bone-resorbing cells and, together with bone-forming osteoblasts, they are responsible for maintaining healthy bones. When cancer cells invade into the bone, however, osteoclasts assist in cancer progression and stimulate bone loss. In this study, we converted the bone-destructive action of osteoclasts by activating their Wnt signaling and generated an osteoclast-derived, bone-protective, tumor-suppressive conditioned medium. The conditioned medium was able to suppress tumor growth and bone loss in a mouse model of mammary tumors and bone metastasis. The described approach is expected to add a novel strategy to treat primary breast cancer as well as bone metastasis. Abstract Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.
Collapse
|
|
20
|
Li Q, Yu H, Sun M, Yang P, Hu X, Ao Y, Cheng J. The tissue origin effect of extracellular vesicles on cartilage and bone regeneration. Acta Biomater 2021; 125:253-266. [PMID: 33657452 DOI: 10.1016/j.actbio.2021.02.039] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/22/2021] [Accepted: 02/24/2021] [Indexed: 12/30/2022]
Abstract
Direct implantation of mesenchymal stem cells (MSCs) for cartilage and bone tissue engineering faces challenges, such as immune rejection and loss of cellular viability or functionality. As nanoscale natural particles, exosomes or small extracellular vesicles (EVs) of MSCs have potential to circumvent these problems. It is significant to investigate the impact of the tissue origin of MSCs on the therapeutic bioactivity of their corresponding EVs for cartilage and bone regeneration. Here, rat MSCs isolated from the adipose, bone marrow, and synovium are cultured to obtain their corresponding EVs (ADSC-EVs, BMSC-EVs, and SMSC-EVs, respectively). The ADSC-EVs stimulate the migration, proliferation, and chondrogenic and osteogenic differentiation of BMSCs in vitro as well as cartilage and bone regeneration in a mouse model more than the BMSC-EVs or SMSC-EVs. Proteomics analysis reveals that the tissue origin contributes to the distinct protein profiles among the three types of EVs, which induced cartilage and bone regenerative capacities by potential mechanisms of regulating signaling pathways including focal adhesion, ECM-receptor interaction, actin cytoskeleton, cAMP, and PI3K-Akt signaling pathways. Consequently, these findings provide insight that the adipose may be a superior candidate in EV-based nanomedicine for cartilage and bone regeneration. STATEMENT OF SIGNIFICANCE: Extracelluar vesicles (EVs) of mesenchymal stem cells (MSCs) have been considered as a promising approach in cartilage and bone tissue engineering. In this study, for the first time, we investigated the tissue origin effect of EVs on chondrogenesis and osteogenesis of MSCs in vitro and in vivo. The results demonstrated that EVs of adipose-derived MSCs showed the most efficiency. Meanwhile, protein proteomics revealed the potential mechanisms. We provide a novel evidence that the adipose is a superior reservoir in EV-based nanotechnologies and biomaterials for cartilage and bone regeneration.
Collapse
Affiliation(s)
- Qi Li
- Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Huilei Yu
- Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Muyang Sun
- Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Peng Yang
- Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Xiaoqing Hu
- Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Yingfang Ao
- Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China.
| | - Jin Cheng
- Department of Sports Medicine, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China.
| |
Collapse
|
|
21
|
Tooley JG, Catlin JP, Schaner Tooley CE. CREB-mediated transcriptional activation of NRMT1 drives muscle differentiation. Transcription 2021; 12:72-88. [PMID: 34403304 PMCID: PMC8555533 DOI: 10.1080/21541264.2021.1963627] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/29/2022] Open
Abstract
The N-terminal methyltransferase NRMT1 is an important regulator of protein/DNA interactions and plays a role in many cellular processes, including mitosis, cell cycle progression, chromatin organization, DNA damage repair, and transcriptional regulation. Accordingly, loss of NRMT1 results in both developmental pathologies and oncogenic phenotypes. Though NRMT1 plays such important and diverse roles in the cell, little is known about its own regulation. To better understand the mechanisms governing NRMT1 expression, we first identified its predominant transcriptional start site and minimal promoter region with predicted transcription factor motifs. We then used a combination of luciferase and binding assays to confirm CREB1 as the major regulator of NRMT1 transcription. We tested which conditions known to activate CREB1 also activated NRMT1 transcription, and found CREB1-mediated NRMT1 expression was increased during recovery from serum starvation and muscle cell differentiation. To determine how NRMT1 expression affects myoblast differentiation, we used CRISPR/Cas9 technology to knock out NRMT1 expression in immortalized C2C12 mouse myoblasts. C2C12 cells depleted of NRMT1 lacked Pax7 expression and were unable to proceed down the muscle differentiation pathway. Instead, they took on characteristics of C2C12 cells that have transdifferentiated into osteoblasts, including increased alkaline phosphatase and type I collagen expression and decreased proliferation. These data implicate NRMT1 as an important downstream target of CREB1 during muscle cell differentiation.
Collapse
Affiliation(s)
- John G. Tooley
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - James P. Catlin
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Christine E. Schaner Tooley
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| |
Collapse
|
|
22
|
Porwal K, Pal S, Bhagwati S, Siddiqi MI, Chattopadhyay N. Therapeutic potential of phosphodiesterase inhibitors in the treatment of osteoporosis: Scopes for therapeutic repurposing and discovery of new oral osteoanabolic drugs. Eur J Pharmacol 2021; 899:174015. [PMID: 33711307 DOI: 10.1016/j.ejphar.2021.174015] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 02/19/2021] [Accepted: 03/03/2021] [Indexed: 01/05/2023]
Abstract
Cyclic nucleotide phosphodiesterases (PDEs) are ubiquitously expressed enzymes that hydrolyze phosphodiester bond in the second messenger molecules including cAMP and cGMP. A wide range of drugs blocks one or more PDEs thereby preventing the inactivation of cAMP/cGMP. PDEs are differentially expressed in bone cells including osteoblasts, osteoclasts and chondrocytes. Intracellular increases in cAMP/cGMP levels in osteoblasts result in osteogenic response. Acting via the type 1 PTH receptor, teriparatide and abaloparatide increase intracellular cAMP and induce osteoanabolic effect, and many PDE inhibitors mimic this effect in preclinical studies. Since all osteoanabolic drugs are injectable and that oral drugs are considered to improve the treatment adherence and persistence, osteogenic PDE inhibitors could be a promising alternative to the currently available osteogenic therapies and directly assessed clinically in drug repurposing mode. Similar to teriparatide/abaloparatide, PDE inhibitors while stimulating osteoblast function also promote osteoclast function through stimulation of receptor activator of nuclear factor kappa-B ligand production from osteoblasts. In this review, we critically discussed the effects of PDE inhibitors in bone cells from cellular signalling to a variety of preclinical models that evaluated the bone formation mechanisms. We identified pentoxifylline (a non-selective PDE inhibitor) and rolipram (a PDE4 selective inhibitor) being the most studied inhibitors with osteogenic effect in preclinical models of bone loss at ≤ human equivalent doses, which suggest their potential for post-menopausal osteoporosis treatment through therapeutic repurposing. Subsequently, we treated pentoxifylline and rolipram as prototypical osteogenic PDEs to predict new chemotypes via the computer-aided design strategies for new drugs, based on the structural biology of PDEs.
Collapse
Affiliation(s)
- Konica Porwal
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), India
| | - Subhashis Pal
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), India
| | - Sudha Bhagwati
- Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Sector 10/1 Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India
| | - Mohd Imran Siddiqi
- Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Sector 10/1 Jankipuram Extension, Sitapur Road, Lucknow, 226 031, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), India.
| |
Collapse
|
|
23
|
Bosch-Rué E, Diez-Tercero L, Giordano-Kelhoffer B, Delgado LM, Bosch BM, Hoyos-Nogués M, Mateos-Timoneda MA, Tran PA, Gil FJ, Perez RA. Biological Roles and Delivery Strategies for Ions to Promote Osteogenic Induction. Front Cell Dev Biol 2021; 8:614545. [PMID: 33520992 PMCID: PMC7841204 DOI: 10.3389/fcell.2020.614545] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 12/17/2020] [Indexed: 12/11/2022] Open
Abstract
Bone is the most studied tissue in the field of tissue regeneration. Even though it has intrinsic capability to regenerate upon injury, several pathologies and injuries could hamper the highly orchestrated bone formation and resorption process. Bone tissue engineering seeks to mimic the extracellular matrix of the tissue and the different biochemical pathways that lead to successful regeneration. For many years, the use of extrinsic factors (i.e., growth factors and drugs) to modulate these biological processes have been the preferred choice in the field. Even though it has been successful in some instances, this approach presents several drawbacks, such as safety-concerns, short release profile and half-time life of the compounds. On the other hand, the use of inorganic ions has attracted significant attention due to their therapeutic effects, stability and lower biological risks. Biomaterials play a key role in such strategies where they serve as a substrate for the incorporation and release of the ions. In this review, the methodologies used to incorporate ions in biomaterials is presented, highlighting the osteogenic properties of such ions and the roles of biomaterials in controlling their release.
Collapse
Affiliation(s)
- Elia Bosch-Rué
- Bioengineering Institute of Technology, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Leire Diez-Tercero
- Bioengineering Institute of Technology, Universitat Internacional de Catalunya, Barcelona, Spain
| | | | - Luis M. Delgado
- Bioengineering Institute of Technology, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Begoña M. Bosch
- Bioengineering Institute of Technology, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Mireia Hoyos-Nogués
- Bioengineering Institute of Technology, Universitat Internacional de Catalunya, Barcelona, Spain
| | | | - Phong A. Tran
- Centre for Biomedical Technologies, Queensland University of Technology (QUT), Brisbane, QLD, Australia
- Interface Science and Materials Engineering Group, School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Brisbane, QLD, Australia
| | - Francisco Javier Gil
- Bioengineering Institute of Technology, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Roman A. Perez
- Bioengineering Institute of Technology, Universitat Internacional de Catalunya, Barcelona, Spain
| |
Collapse
|
|
24
|
Ro HS, Park HJ, Seo YK. Fluorine-incorporated TiO 2 nanotopography enhances adhesion and differentiation through ERK/CREB pathway. J Biomed Mater Res A 2020; 109:1406-1417. [PMID: 33253478 PMCID: PMC8247403 DOI: 10.1002/jbm.a.37132] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 11/25/2020] [Accepted: 11/28/2020] [Indexed: 12/25/2022]
Abstract
This study compared the topography of different titanium surface structures (TiO2 nanotube and grain) with similar elemental compositions (TiO2 and fluorine [F]) on the Ti surface. High magnification indicated that the surfaces of the control and etching groups were similar to each other in a flat, smooth form. The group anodized for 1 h was observed with TiO2 nanotubes organized very neatly and regularly. In the group anodized for 30 min after etching, uneven wave and nanopore structures were observed. In addition, MTT assay showed that the F of the surface did not adversely affect cell viability, and the initial cell adhesion was increased in the 2.8% F‐incorporated TiO2 nanograin. At the edge of adherent cells, filopodia were observed in spreading form on the surfaces of the anodizing and two‐step processing groups, and they were observed in a branch shape in the control and etching groups. Moreover, cell adhesion molecule and osteogenesis marker expression was increased at the F‐incorporated TiO2 nanostructure. In addition, it was found that the expression of p‐extracellular signal‐regulated kinase (ERK) and p‐cAMP response element‐binding protein (CREB) increased in the TiO2 nanograin with the nanopore surface compared to the micro rough and nanotube surfaces relative to the osteogenic‐related gene expression patterns. As a result, this study confirmed that the topographic structure of the surface is more affected by osteogenic differentiation than the pore size and that differentiation by specific surface composition components is by CREB. Thus, the synergy effect of osteogenic differentiation was confirmed by the simultaneous activation of CREB/ERK.
Collapse
Affiliation(s)
- Hyang-Seon Ro
- Department of Chemical and Biochemical Engineering, Dongguk University, Seoul, South Korea
| | - Hee-Jung Park
- Department of Medical Biotechnology (BK21 Plus team), Dongguk University, Gyeonggi-do, South Korea
| | - Young-Kwon Seo
- Department of Medical Biotechnology (BK21 Plus team), Dongguk University, Gyeonggi-do, South Korea
| |
Collapse
|
|
25
|
Zhang J, Zhao IS, Yu OY, Li Q, Mei ML, Zhang C, Chu CH. Layer-by-layer self-assembly polyelectrolytes loaded with cyclic adenosine monophosphate enhances the osteo/odontogenic differentiation of stem cells from apical papilla. J Biomed Mater Res A 2020; 109:207-218. [PMID: 32441418 DOI: 10.1002/jbm.a.37017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 04/02/2020] [Accepted: 04/19/2020] [Indexed: 12/26/2022]
Abstract
Cyclic adenosine monophosphate (cAMP) is a second messenger involved in the dental regeneration. However, efficient long-lasting delivery of cAMP that is sufficient to mimic the in vivo microenvironment remains a major challenge. Here, cAMP was loaded in stem cells from apical papilla (SCAPs) using layer-by-layer self-assembly with gelatin and alginate polyelectrolytes (LBL-cAMP-SCAPs). LBL-cAMP-SCAPs expressed cAMP and increased the phosphorylation level of cAMP-response element-binding protein (CREB) which were evaluated by immunofluorescence and western blotting (WB). Enzyme-linked immunosorbent assay (ELISA) demonstrated that a sustained release of cAMP and vascular endothelial growth factor (VEGF) were present up to 14 days. Scanning electron microscopy (SEM) found LBL-coated SCAPs exhibited a spheroid-like morphology. CCK8 and live/dead staining showed that LBL treatment had no significant effect on cell proliferation and viability. LBL-cAMP-SCAPs enhanced mineralized nodule formation and up-regulated the mRNA levels of the osteogenesis-related genes, as well as related transcription factor-2 protein level which were revealed by Alizarin red staining, RT-PCR and WB, respectively. In conclusion, LBL self-assembly loaded with cAMP promoted the osteo/odontogenic differentiation of SCAPs, thereby providing a potential strategy for bioactive molecular delivery in dental regeneration.
Collapse
Affiliation(s)
- Jing Zhang
- Key Laboratory of Oral Disease Research of Anhui Province, Stomatologic Hospital and College, Anhui Medical University, Hefei, China.,Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Irene ShuPing Zhao
- School of Stomatology, Shenzhen University Health Science Center, Shenzhen, China
| | - Ollie YiRu Yu
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - QuanLi Li
- Key Laboratory of Oral Disease Research of Anhui Province, Stomatologic Hospital and College, Anhui Medical University, Hefei, China
| | - May Lei Mei
- Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - ChengFei Zhang
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Chun Hung Chu
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
26
|
Rumiński S, Kalaszczyńska I, Lewandowska-Szumieł M. Effect of cAMP Signaling Regulation in Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells. Cells 2020; 9:E1587. [PMID: 32629962 PMCID: PMC7408391 DOI: 10.3390/cells9071587] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 06/25/2020] [Accepted: 06/26/2020] [Indexed: 12/16/2022] Open
Abstract
The successful implementation of adipose-derived mesenchymal stem cells (ADSCs) in bone regeneration depends on efficient osteogenic differentiation. However, a literature survey and our own experience demonstrated that current differentiation methods are not effective enough. Since the differentiation of mesenchymal stem cells (MSCs) into osteoblasts and adipocytes can be regulated by cyclic adenosine monophosphate (cAMP) signaling, we investigated the effects of cAMP activator, forskolin, and inhibitor, SQ 22,536, on the early and late osteogenic differentiation of ADSCs cultured in spheroids or in a monolayer. Intracellular cAMP concentration, protein kinase A (PKA) activity, and inhibitor of DNA binding 2 (ID2) expression examination confirmed cAMP up- and downregulation. cAMP upregulation inhibited the cell cycle and protected ADSCs from osteogenic medium (OM)-induced apoptosis. Surprisingly, the upregulation of cAMP level at the early stages of osteogenic differentiation downregulated the expression of osteogenic markers RUNX2, Osterix, and IBSP, which was more significant in spheroids, and it is used for the more efficient commitment of ADSCs into preosteoblasts, according to the previously reported protocol. However, cAMP upregulation in a culture of ADSCs in spheroids resulted in significantly increased osteocalcin production and mineralization. Thus, undifferentiated and predifferentiated ADSCs respond differently to cAMP pathway stimulation in terms of osteogenesis, which might explain the ambiguous results from the literature.
Collapse
Affiliation(s)
- Sławomir Rumiński
- Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland;
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Ilona Kalaszczyńska
- Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland;
- Laboratory for Cell Research and Application, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Małgorzata Lewandowska-Szumieł
- Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland;
- Laboratory for Cell Research and Application, Medical University of Warsaw, 02-097 Warsaw, Poland
| |
Collapse
|
|
27
|
Kuttappan S, Jo JI, Sabu CK, Menon D, Tabata Y, Nair MB. Bioinspired nanocomposite fibrous scaffold mediated delivery of ONO-1301 and BMP2 enhance bone regeneration in critical sized defect. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 110:110591. [DOI: 10.1016/j.msec.2019.110591] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/19/2019] [Accepted: 12/21/2019] [Indexed: 01/08/2023]
|
|
28
|
Sun P, He L, Jia K, Yue Z, Li S, Jin Y, Li Z, Siwko S, Xue F, Su J, Liu M, Luo J. Regulation of body length and bone mass by Gpr126/Adgrg6. SCIENCE ADVANCES 2020; 6:eaaz0368. [PMID: 32219165 PMCID: PMC7083604 DOI: 10.1126/sciadv.aaz0368] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 12/26/2019] [Indexed: 05/24/2023]
Abstract
Adhesion G protein-coupled receptor G6 (Adgrg6; also named GPR126) single-nucleotide polymorphisms are associated with human height in multiple populations. However, whether and how GPR126 regulates body height is unknown. In this study, we found that mouse body length was specifically decreased in Osx-Cre;Gpr126fl/fl mice. Deletion of Gpr126 in osteoblasts resulted in a remarkable delay in osteoblast differentiation and mineralization during embryonic bone formation. Postnatal bone formation, bone mass, and bone strength were also significantly affected in Gpr126 osteoblast deletion mice because of defects in osteoblast proliferation, differentiation, and ossification. Furthermore, type IV collagen functioned as an activating ligand of Gpr126 to regulate osteoblast differentiation and function by stimulating cAMP signaling. Moreover,the cAMP activator PTH(1-34), could partially restore the inhibition of osteoblast differentiation and the body length phenotype induced by Gpr126 deletion.Together, our results demonstrated that COLIV-Gpr126 regulated body length and bone mass through cAMP-CREB signaling pathway.
Collapse
Affiliation(s)
- Peng Sun
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
- The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of the Ministry of Education, East China Normal University, Shanghai 200241, P.R. China
| | - Liang He
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
| | - Kunhang Jia
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
| | - Zhiying Yue
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
| | - Shichang Li
- The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of the Ministry of Education, East China Normal University, Shanghai 200241, P.R. China
| | - Yunyun Jin
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
| | - Zhenxi Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
| | - Stefan Siwko
- Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA
| | - Feng Xue
- Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Fengxian District Central Hospital, Shanghai 201400, P.R. China
| | - Jiacan Su
- Department of Orthopaedics Trauma, Changhai Hospital, Second Military Medical University, Shanghai, P.R. China
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
| | - Jian Luo
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China
| |
Collapse
|
|
29
|
Yu W, Chen FC, Xu WN, Ding SL, Chen PB, Yang L, Jiang SD, Pan XY. Inhibition of Y1 Receptor Promotes Osteogenesis in Bone Marrow Stromal Cells via cAMP/PKA/CREB Pathway. Front Endocrinol (Lausanne) 2020; 11:583105. [PMID: 33240219 PMCID: PMC7683715 DOI: 10.3389/fendo.2020.583105] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/14/2020] [Indexed: 11/13/2022] Open
Abstract
Inhibition of neuropeptide Y1 receptor stimulates osteogenesis in vitro and in vivo. However, the underlying mechanisms involved in these effects remain poorly understood. Here we identify the effects of Y1 receptor deficiency on osteogenic differentiation in human bone marrow stromal cells (BMSCs) by using genetic and pharmacological regulation, and to explore the pathways mediating these effects. In BMSCs, inhibition of Y1 receptor stimulates osteogenesis and upregulates the expression levels of the master transcriptional factor RUNX2. Mechanistically, Y1 receptor deficiency increases the levels of intracellular cAMP, which via protein kinase A (PKA) mediated pathways results in activation of phospho-CREB (p-CREB). We find RUNX2 activation induced by Y1 receptor deficiency is reversed by H-89, a PKA inhibitor. These results indicate Y1 receptor deficiency activates PKA-mediated phosphorylation of CREB, leading to activation of RUNX2 and enhances osteogenic differentiation in BMSCs. In conclusion, these data indicate that Y1 receptor deficiency promotes osteogenic differentiation by RUNX2 stimulation through cAMP/PKA/CREB pathway.
Collapse
Affiliation(s)
- Wei Yu
- Department of Orthopaedic Surgery, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Fan-Cheng Chen
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Ning Xu
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Sheng-Long Ding
- Department of Orthopaedic, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peng-Bo Chen
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Lei Yang
- Department of Orthopaedic Surgery, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sheng-Dan Jiang
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- *Correspondence: Xiao-Yun Pan, ; Sheng-Dan Jiang,
| | - Xiao-Yun Pan
- Department of Orthopaedic Surgery, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Xiao-Yun Pan, ; Sheng-Dan Jiang,
| |
Collapse
|
|
30
|
Gioldasi S, Karvela A, Rojas-Gil AP, Rodi M, de Lastic AL, Thomas I, Spiliotis BE, Mouzaki A. Metabolic Association between Leptin and the Corticotropin Releasing Hormone. Endocr Metab Immune Disord Drug Targets 2020; 19:458-466. [PMID: 30727936 PMCID: PMC7360915 DOI: 10.2174/1871530319666190206165626] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 10/31/2018] [Accepted: 12/27/2018] [Indexed: 01/29/2023]
Abstract
Objective In healthy individuals, leptin is produced from adipose tissue and is secreted into the circulation to communicate energy balance status to the brain and control fat metabolism. Corticotropin-Releasing Hormone (CRH) is synthesized in the hypothalamus and regulates stress responses. Among the many adipokines and hormones that control fat metabolism, leptin and CRH both curb appetite and inhibit food intake. Despite numerous reports on leptin and CRH properties and function, little has been actually shown about their association in the adipose tissue environment. Methods In this article, we summarized the salient information on leptin and CRH in relation to metabolism. We also investigated the direct effect of recombinant CRH on leptin secretion by primary cultures of human adipocytes isolated from subcutaneous abdominal adipose tissue of 7 healthy children and adolescents, and measured CRH and leptin levels in plasma collected from peripheral blood of 24 healthy children and adolescents to assess whether a correlation exists between CRH and leptin levels in the periphery. Results and Conclusion The available data indicate that CRH exerts a role in the regulation of leptin in human adipocytes. We show that CRH downregulates leptin production by mature adipocytes and that a strong negative correlation exists between CRH and leptin levels in the periphery, and suggest the possible mechanisms of CRH control of leptin. Delineation of CRH control of leptin production by adipocytes may explain unknown pathogenic mechanisms linking stress and metabolism.
Collapse
Affiliation(s)
- Sofia Gioldasi
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Alexia Karvela
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Medical School, University of Patras, Patras, Greece
| | | | - Maria Rodi
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Anne-Lise de Lastic
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Iason Thomas
- Department of Allergy, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Bessie E Spiliotis
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Medical School, University of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| |
Collapse
|
|
31
|
Kuttappan S, Jo JI, Menon D, Ishimoto T, Nakano T, Nair SV, Tabata Y, Nair MB. ONO-1301 loaded nanocomposite scaffolds modulate cAMP mediated signaling and induce new bone formation in critical sized bone defect. Biomater Sci 2019; 8:884-896. [PMID: 31822874 DOI: 10.1039/c9bm01352k] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent studies on bone regeneration demonstrate the use of low cost and stable small molecules, which avoid the adverse effect and high cost of growth factors. Herein, we investigate the chemotactic, angiogenic and osteoinductive potential of a prostacyclin analogue, ONO-1301, when delivered through a biomimetic nanocomposite scaffold (nanohydroxyapatite-gelatin matrix reinforced with fibers) for bone tissue regeneration. The small molecule was loaded onto the scaffold in three different concentrations. There was burst release from all the groups of scaffolds within 24 h followed by a sustained release up to 14 days, but the concentration was dependent on loading percentage. ONO-1301 loaded scaffolds augmented the migration, proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs), but increasing the concentration beyond a certain dose did not show any effect. The osteoinduction was mediated through the prostaglandin I2 receptor and cyclic AMP (cAMP) signaling pathway. They also promoted new bone formation in large sized calvarial defects in rats compared to the scaffold alone, but did not show any impact on angiogenesis. Hence, this study suggests the chemotactic and osteoinductive capability of ONO-1301 for the repair and regeneration of critical sized bone defects.
Collapse
Affiliation(s)
- Shruthy Kuttappan
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham, India.
| | - Jun-Ichiro Jo
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Japan.
| | - Deepthy Menon
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham, India.
| | - Takuya Ishimoto
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, Osaka, Japan
| | - Takayoshi Nakano
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, Osaka, Japan
| | - Shantikumar V Nair
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham, India.
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Japan.
| | - Manitha B Nair
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham, India.
| |
Collapse
|
|
32
|
Salt-inducible kinase 1 regulates bone anabolism via the CRTC1-CREB-Id1 axis. Cell Death Dis 2019; 10:826. [PMID: 31672960 PMCID: PMC6823377 DOI: 10.1038/s41419-019-1915-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/21/2019] [Accepted: 08/20/2019] [Indexed: 12/11/2022]
Abstract
New bone anabolic agents for the effective treatment of bone metabolic diseases like osteoporosis are of high clinical demand. In the present study, we reveal the function of salt-inducible kinase 1 (SIK1) in regulating osteoblast differentiation. Gene knockdown of SIK1 but not of SIK2 or SIK3 expression in primary preosteoblasts increased osteoblast differentiation and bone matrix mineralization. SIK1 also regulated the proliferation of osteoblastic precursor cells in osteogenesis. This negative control of osteoblasts required the catalytic activity of SIK1. SIK1 phosphorylated CREB regulated transcription coactivator 1 (CRTC1), preventing CRTC1 from enhancing CREB transcriptional activity for the expression of osteogenic genes like Id1. Furthermore, SIK1 knockout (KO) mice had higher bone mass, osteoblast number, and bone formation rate versus littermate wild-type (WT) mice. Preosteoblasts from SIK1 KO mice showed more osteoblastogenic potential than did WT cells, whereas osteoclast generation among KO and WT precursors was indifferent. In addition, bone morphogenic protein 2 (BMP2) suppressed both SIK1 expression as well as SIK1 activity by protein kinase A (PKA)–dependent mechanisms to stimulate osteogenesis. Taken together, our results indicate that SIK1 is a key negative regulator of preosteoblast proliferation and osteoblast differentiation and that the repression of SIK1 is crucial for BMP2 signaling for osteogenesis. Therefore, we propose SIK1 to be a useful therapeutic target for the development of bone anabolic strategies.
Collapse
|
|
33
|
Fujino S, Hamano S, Tomokiyo A, Itoyama T, Hasegawa D, Sugii H, Yoshida S, Washio A, Nozu A, Ono T, Wada N, Kitamura C, Maeda H. Expression and function of dopamine in odontoblasts. J Cell Physiol 2019; 235:4376-4387. [PMID: 31612496 DOI: 10.1002/jcp.29314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/30/2019] [Indexed: 11/07/2022]
Abstract
Dopamine (DA) is produced from tyrosine by tyrosine hydroxylase (TH). A recent study has reported that DA promotes the mineralization of murine preosteoblasts. However, the role of DA in odontoblasts has not been examined. Therefore, in this investigation, we researched the expression of TH and DA in odontoblasts and the effects of DA on the differentiation of preodontoblasts (KN-3 cells). Immunostaining showed that TH and DA were intensely expressed in odontoblasts and preodontoblasts of rat incisors and molars. KN-3 cells expressed D1-like and D2-like receptors for DA. Furthermore, DA promoted odontoblastic differentiation of KN-3 cells, whereas an antagonist of D1-like receptors and a PKA signaling blocker, inhibited such differentiation. However, antagonists of D2-like receptors promoted differentiation. These results suggested that DA in preodontoblasts and odontoblasts might promote odontoblastic differentiation through D1-like receptors, but not D2-like receptors, and PKA signaling in an autocrine or paracrine manner and plays roles in dentinogenesis.
Collapse
Affiliation(s)
- Shoko Fujino
- Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Sayuri Hamano
- Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.,OBT Research Center, Kyushu University, Fukuoka, Japan
| | - Atsushi Tomokiyo
- Department of Endodontology, Kyushu University Hospital, Fukuoka, Japan
| | - Tomohiro Itoyama
- Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Daigaku Hasegawa
- Department of Endodontology, Kyushu University Hospital, Fukuoka, Japan
| | - Hideki Sugii
- Department of Endodontology, Kyushu University Hospital, Fukuoka, Japan
| | | | - Ayako Washio
- Division of Endodontics and Restorative Density, Department of Science of Oral Functions, Kyushu Dental University, Fukuoka, Japan
| | - Aoi Nozu
- Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Taiga Ono
- Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Naohisa Wada
- Division of General Dentistry, Kyushu University Hospital, Fukuoka, Japan
| | - Chiaki Kitamura
- Division of Endodontics and Restorative Density, Department of Science of Oral Functions, Kyushu Dental University, Fukuoka, Japan
| | - Hidefumi Maeda
- Department of Endodontology and Operative Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.,Department of Endodontology, Kyushu University Hospital, Fukuoka, Japan
| |
Collapse
|
|
34
|
Zhang J, Zhang CF, Li QL, Chu CH. Cyclic Adenosine Monophosphate Promotes Odonto/Osteogenic Differentiation of Stem Cells from the Apical Papilla via Suppression of Transforming Growth Factor Beta 1 Signaling. J Endod 2019; 45:150-155. [PMID: 30711170 DOI: 10.1016/j.joen.2018.10.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 08/14/2018] [Accepted: 10/18/2018] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Stem cells from the apical papilla (SCAPs) possess strong odonto/osteogenic differentiation potential. This study investigated the effect of cyclic adenosine monophosphate (cAMP) on odonto/osteogenic differentiation of SCAPs and the underlining interplay between cAMP and transforming growth factor beta 1 (TGF-β1). METHODS SCAPs were stimulated with an activator of cAMP (forskolin) in the presence of either TGF-β1 or a TGF-β1 inhibitor. The amounts of calcium mineral deposition and alkaline phosphatase activity were determined. Quantitative real-time polymerase chain reaction was performed to elucidate cAMP on the TGF-β1-mediated odonto/osteogenic differentiation of SCAPs. The effect of cAMP on the phosphorylation of Smad2/Smad3 and extracellular-regulated kinase (ERK)/P38 induced by TGF-β1 was analyzed by Western blotting. RESULTS Cotreatment with forskolin and a TGF-β1 inhibitor enhanced alkaline phosphatase activity and deposition of calcium minerals in SCAPs. Moreover, the TGF-β1 inhibitor synergized the effect of forskolin on the expression of type I collagen and runt-related transcription factor 2. The results of Western blotting revealed that forskolin attenuated the unregulated expression of the phosphorylation of Smad3 and ERK induced by TGF-β1, and a cAMP inhibitor (H89) antagonized this effect. CONCLUSIONS This study showed that cAMP signaling exerts its up-regulating effects on the odonto/osteogenic differentiation of SCAPs by interfering with TGF-β1 signaling via inhibiting Smad3 and ERK phosphorylation.
Collapse
Affiliation(s)
- Jing Zhang
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, China; Key Laboratory of Oral Disease Research of Anhui Province, Stomatological Hospital and College, Anhui Medical University, Hefei, China
| | - Cheng Fei Zhang
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
| | - Quan Li Li
- Key Laboratory of Oral Disease Research of Anhui Province, Stomatological Hospital and College, Anhui Medical University, Hefei, China
| | - Chun Hung Chu
- Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
35
|
Gao B, Deng R, Chai Y, Chen H, Hu B, Wang X, Zhu S, Cao Y, Ni S, Wan M, Yang L, Luo Z, Cao X. Macrophage-lineage TRAP+ cells recruit periosteum-derived cells for periosteal osteogenesis and regeneration. J Clin Invest 2019; 129:2578-2594. [PMID: 30946695 DOI: 10.1172/jci98857] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The periosteum, a thin tissue that covers almost the entire bone surface, accounts for more than 80% of human bone mass and is essential for bone regeneration. Its osteogenic and bone regenerative abilities are well studied, but much is unknown about the periosteum. In this study, we found that macrophage-lineage cells recruit periosteum-derived cells (PDCs) for cortical bone formation. Knockout of colony stimulating factor-1 eliminated macrophage-lineage cells and resulted in loss of PDCs with impaired periosteal bone formation. Moreover, macrophage-lineage TRAP+ cells induced transcriptional expression of periostin and recruitment of PDCs to the periosteal surface through secretion of platelet-derived growth factor-BB (PDGF-BB), where the recruited PDCs underwent osteoblast differentiation coupled with type H vessel formation. We also found that subsets of Nestin+ and LepR+ PDCs possess multipotent and self-renewal abilities and contribute to cortical bone formation. Nestin+ PDCs are found primarily during bone development, whereas LepR+ PDCs are essential for bone homeostasis in adult mice. Importantly, conditional knockout of Pdgfrβ (platelet-derived growth factor receptor beta) in LepR+ cells impaired periosteal bone formation and regeneration. These findings uncover the essential role of periosteal macrophage-lineage cells in regulating periosteum homeostasis and regeneration.
Collapse
Affiliation(s)
- Bo Gao
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Institute of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ruoxian Deng
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yu Chai
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hao Chen
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Bo Hu
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Xiao Wang
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Shouan Zhu
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yong Cao
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Shuangfei Ni
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mei Wan
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Liu Yang
- Institute of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhuojing Luo
- Institute of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xu Cao
- Department of Orthopaedic Surgery, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
36
|
Yang Y, Dong F, Liu X, Xu J, Wu X, Wang D, Zheng Y. Developmental toxicity by thifluzamide in zebrafish (Danio rerio): Involvement of leptin. CHEMOSPHERE 2019; 221:863-869. [PMID: 30703632 DOI: 10.1016/j.chemosphere.2019.01.043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 01/03/2019] [Accepted: 01/06/2019] [Indexed: 06/09/2023]
Abstract
Although previous trials have indicated that thifluzamide induces developmental inhibition in zebrafish, understanding the distinct mechanism of thifluzamide in this process remains challenging. This study investigated the effect of thifluzamide on zebrafish development and the underlying related signaling pathway. Thifluzamide repressed glucagon (GC) levels but increased growth hormone (GH) levels, and changed the expression of the genes related to growth and development. Additionally, protein kinase A (PKA) and leptin levels were obviously decreased in zebrafish after exposure to thifluzamide for 28 days, but the phosphorylation of cAMP responsive element-binding protein (CREB) was increased. Our results suggested that the anti-developmental effects of thifluzamide in zebrafish are largely associated with alterations in expressions of genes related to growth and development through modulation of leptin.
Collapse
Affiliation(s)
- Yang Yang
- State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, People's Republic of China
| | - Fengshou Dong
- State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, People's Republic of China
| | - Xingang Liu
- State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, People's Republic of China
| | - Jun Xu
- State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, People's Republic of China
| | - Xiaohu Wu
- State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, People's Republic of China
| | - Donghui Wang
- Plant Developmental Biology, College of Life Sciences, Peking University, 5 Yiheyuan Road, Beijing 100871, China
| | - Yongquan Zheng
- State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, People's Republic of China.
| |
Collapse
|
|
37
|
Wang YY, Pu XY, Shi WG, Fang QQ, Chen XR, Xi HR, Gao YH, Zhou J, Xian CJ, Chen KM. Pulsed electromagnetic fields promote bone formation by activating the sAC-cAMP-PKA-CREB signaling pathway. J Cell Physiol 2019; 234:2807-2821. [PMID: 30067871 DOI: 10.1002/jcp.27098] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023]
Abstract
The application of pulsed electromagnetic fields (PEMFs) in the prevention and treatment of osteoporosis has long been an area of interest. However, the clinical application of PEMFs remains limited because of the poor understanding of the PEMF action mechanism. Here, we report that PEMFs promote bone formation by activating soluble adenylyl cyclase (sAC), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and cAMP response element-binding protein (CREB) signaling pathways. First, it was found that 50 Hz 0.6 millitesla (mT) PEMFs promoted osteogenic differentiation of rat calvarial osteoblasts (ROBs), and that PEMFs activated cAMP-PKA-CREB signaling by increasing intracellular cAMP levels, facilitating phosphorylation of PKA and CREB, and inducing nuclear translocation of phosphorylated (p)-CREB. Blocking the signaling by adenylate cyclase (AC) and PKA inhibitors both abolished the osteogenic effect of PEMFs. Second, expression of sAC isoform was found to be increased significantly by PEMF treatment. Blocking sAC using sAC-specific inhibitor KH7 dramatically inhibited the osteogenic differentiation of ROBs. Finally, the peak bone mass of growing rats was significantly increased after 2 months of PEMF treatment with 90 min/day. The serum cAMP content, p-PKA, and p-CREB as well as the sAC protein expression levels were all increased significantly in femurs of treated rats. The current study indicated that PEMFs promote bone formation in vitro and in vivo by activating sAC-cAMP-PKA-CREB signaling pathway of osteoblasts directly or indirectly.
Collapse
Affiliation(s)
- Yuan-Yuan Wang
- Department of Bioengineering, School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, China
- Institute of Orthopaedics, Lanzhou General Hospital of CPLA, Lanzhou, China
| | - Xiu-Ying Pu
- Department of Bioengineering, School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, China
| | - Wen-Gui Shi
- Institute of Orthopaedics, Lanzhou General Hospital of CPLA, Lanzhou, China
| | - Qing-Qing Fang
- Institute of Orthopaedics, Lanzhou General Hospital of CPLA, Lanzhou, China
| | - Xin-Ru Chen
- Department of Biology, College of Life Sciences, Northwest A & F University, Yanglin, China
| | - Hui-Rong Xi
- Institute of Orthopaedics, Lanzhou General Hospital of CPLA, Lanzhou, China
| | - Yu-Hai Gao
- Institute of Orthopaedics, Lanzhou General Hospital of CPLA, Lanzhou, China
| | - Jian Zhou
- Institute of Orthopaedics, Lanzhou General Hospital of CPLA, Lanzhou, China
| | - Cory J Xian
- Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
| | - Ke-Ming Chen
- Institute of Orthopaedics, Lanzhou General Hospital of CPLA, Lanzhou, China
| |
Collapse
|
|
38
|
Lou D, Ye J, Yang L, Wu Z, Zheng W, Zhang H. Icariin stimulates differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) through activation of cAMP/PKA/CREB. BRAZ J PHARM SCI 2019. [DOI: 10.1590/s2175-97902019000218300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Dan Lou
- Wenzhou Medical University, China
| | | | | | - Zheng Wu
- Harbin University of Commerce, China
| | - Wei Zheng
- Harbin University of Commerce, China
| | | |
Collapse
|
|
39
|
Evaluation of selected traditional Chinese medical extracts for bone mineral density maintenance: A mechanistic study. J Tradit Complement Med 2018; 9:227-235. [PMID: 31193882 PMCID: PMC6544583 DOI: 10.1016/j.jtcme.2017.07.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 07/25/2017] [Indexed: 01/02/2023] Open
Abstract
Objective To investigate the development of a minimal traditional Chinese medicine (TCM) formula using selected TCM ingredients and evaluating their biological activity with bone-specific in vitro tests. Finally, determining if the minimal formula can maintain bone mineral density (BMD) in a low bone mass (LBM)/osteoporosis (OP) model system. Methods and results Sixteen different TCM plant extracts were tested for estrogenic, osteogenic and osteoclastic activities. Despite robust activation of the full-length estrogen receptors α and β by Psoralea corylifolia and Epimedium brevicornu, these extracts do not activate the isolated estrogen ligand binding domains (LBD) of either ERα or ERβ; estrogen (17-β estradiol) fully activates the LBD of ERα and ERβ. E. brevicornu and Drynaria fortunei extracts activated cyclic AMP response elements (CRE) individually and when combined these ingredients stimulated the production of osteoblastic markers Runx2 and Bmp4 in MC3T3-E1 cells. E. brevicornu, Salvia miltiorrhiza, and Astragalus onobrychis extracts inhibited the Il-1β mediated activation of NF-κβ and an E. brevicornu/D. fortunei combination inhibited the development of osteoclasts from precursor cells. Further, a minimal formula containing the E. brevicornu/D. fortunei combination with or without a third ingredient (S. miltiorrhiza, Angelica sinensis, or Lycium barbarum) maintained bone mineral density (BMD) similar to an estradiol-treated control group in the ovariectomized rat; a model LBM/OP system. Conclusion A minimal formula consisting of TCM plant extracts that activate CRE and inhibit of NF-κβ activation, but do not behave like estrogen, maintain BMD in a LBM/OP model system.
Collapse
Key Words
- Anti-inflammatory
- BMD, bone mineral density
- BSA, bovine serum albumin
- Bmp4, bone morphogenic protein 4
- CRE, cyclic adenosine monophosphate response element
- CREB, cyclic adenosine monophosphate response element binding protein
- DEXA, dual-energy X-ray absorptiometry
- DMSO, Dimethyl sulfoxide
- Drynaria fortunei
- E2, estradiol
- ER, estrogen receptor
- ERE, estrogen response element
- Epimedium brevicornu
- Estrogenic
- FBS, fetal bovine serum
- Fsk, forskolin
- Hprt, hypoxanthine-guanine phosphoribosyl-transferase
- IL-1, interleukin 1
- LBD, ligand binding domain
- LBM, low bone mass
- M-CSF, macrophage colony-stimulating factor
- MAPK, mitogen activated protein kinase
- NF-κβ, nuclear factor kappa beta
- OP, osteoporosis
- Osteoporosis
- PTH, parathyroid hormone
- PTHrp, PTH related peptide
- RANKL, receptor activator of nuclear factor kappa beta ligand
- RLU, relative luminescence unit
- ROI, region of interest
- Runx2, runt-related transcription factor 2
- SFM, serum free media
- TCM, traditional Chinese medicine
- TNFα, tumor necrosis factor alpha
- TRAP, tartrate-resistant acid phosphatase
- UAS, upstream activating sequence
- cAMP, cyclic adenosine monophosphate
- qPCR, quantitative polymerase chain reaction
Collapse
|
|
40
|
Kim B, Lee JH, Jin WJ, Kim HH, Ha H, Lee ZH. Trapidil induces osteogenesis by upregulating the signaling of bone morphogenetic proteins. Cell Signal 2018; 49:68-78. [DOI: 10.1016/j.cellsig.2018.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 05/28/2018] [Accepted: 06/03/2018] [Indexed: 11/29/2022]
|
|
41
|
Um J, Lee JH, Jung DW, Williams DR. Re-education begins at home: an overview of the discovery of in vivo-active small molecule modulators of endogenous stem cells. Expert Opin Drug Discov 2018; 13:307-326. [PMID: 29421943 DOI: 10.1080/17460441.2018.1437140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Degenerative diseases, such as Alzheimer's disease, heart disease and arthritis cause great suffering and are major socioeconomic burdens. An attractive treatment approach is stem cell transplantation to regenerate damaged or destroyed tissues. However, this can be problematic. For example, donor cells may not functionally integrate into the host tissue. An alternative methodology is to deliver bioactive agents, such as small molecules, directly into the diseased tissue to enhance the regenerative potential of endogenous stem cells. Areas covered: In this review, the authors discuss the necessity of developing these small molecules to treat degenerative diseases and survey progress in their application as therapeutics. They describe both the successes and caveats of developing small molecules that target endogenous stem cells to induce tissue regeneration. This article is based on literature searches which encompass databases for biomedical research and clinical trials. These small molecules are also categorized per their target disease and mechanism of action. Expert opinion: The development of small molecules targeting endogenous stem cells is a high-profile research area. Some compounds have made the successful transition to the clinic. Novel approaches, such as modulating the stem cell niche or targeted delivery to disease sites, should increase the likelihood of future successes in this field.
Collapse
Affiliation(s)
- JungIn Um
- a New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology , Buk-Gu , Gwangju , Republic of Korea
| | - Ji-Hyung Lee
- a New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology , Buk-Gu , Gwangju , Republic of Korea
| | - Da-Woon Jung
- a New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology , Buk-Gu , Gwangju , Republic of Korea
| | - Darren R Williams
- a New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology , Buk-Gu , Gwangju , Republic of Korea
| |
Collapse
|
|
42
|
Su S, Zhu Y, Li S, Liang Y, Zhang J. The transcription factor cyclic adenosine 3',5'-monophosphate response element-binding protein enhances the odonto/osteogenic differentiation of stem cells from the apical papilla. Int Endod J 2016; 50:885-894. [PMID: 27716996 DOI: 10.1111/iej.12709] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 10/04/2016] [Indexed: 12/15/2022]
Abstract
AIM To investigate the role of cAMP response element-binding protein (CREB) in the regulation of odonto/osteogenic differentiation of stem cells from the apical papilla (SCAPs). METHODOLOGY Stem cells from the apical papilla were obtained from human impacted third molars (n = 15). Isolated SCAPs were transfected with CREB overexpressing/silenced lentivirus. Transfected cells were stained with alizarin red to investigate mineralized nodule formation. The expression of the mineralization-related genes, alkaline phosphatase (ALP), collagen type I (Col I), runt-related transcription factor 2 (RUNX2), osterix (OSX) and osteocalcin (OCN), was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Protein expression of the odontogenic-related marker dentine sialoprotein (DSP) and the osteogenic-related marker RUNX2 was measured by Western blotting analysis. One-way analysis of variance (anova) and Student's t-test were used for statistical analysis (a = 0.05). RESULTS The overexpression of CREB enhanced mineralized nodule formation and up-regulated (P < 0.05) the mRNA levels of odonto/osteogenic-related markers, including ALP, Col I, RUNX2, OSX and OCN, and also increased (P < 0.05) the protein expression of DSP and RUNX2. In contrast, the silencing of CREB inhibited (P < 0.05) the mineralization capacity of the SCAPs and decreased (P < 0.05) the expression of odonto/osteogenic-related markers. CONCLUSION Up-regulation of CREB expression promoted odonto/osteogenic differentiation of SCAPs and provided a potential method for the regeneration of the dentine-pulp complex.
Collapse
Affiliation(s)
- S Su
- Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, China
| | - Y Zhu
- Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, China
| | - S Li
- Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, China
| | - Y Liang
- Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, China
| | - J Zhang
- Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, China
| |
Collapse
|
|
43
|
Li J, Zhang H, Yang C, Li Y, Dai Z. An overview of osteocalcin progress. J Bone Miner Metab 2016; 34:367-79. [PMID: 26747614 DOI: 10.1007/s00774-015-0734-7] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 12/22/2015] [Indexed: 12/20/2022]
Abstract
An increasing amount of data indicate that osteocalcin is an endocrine hormone which regulates energy metabolism, male fertility and brain development. However, the detailed functions and mechanism of osteocalcin are not well understood and conflicting results have been obtained from researchers worldwide. In the present review, we summarize the progress of osteocalcin studies over the past 40 years, focusing on the structure of carboxylated and undercarboxylated osteocalcin, new functions and putative receptors, the role of osteocalcin in bone remodeling, specific expression and regulation in osteoblasts, and new indices for clinical studies. The complexity of osteocalcin in completely, uncompletely and non-carboxylated forms may account for the discrepancies in its tertiary structure and clinical results. Moreover, the extensive expression of osteocalcin and its putative receptor GPRC6A imply that there are new physiological functions and mechanisms of action of osteocalcin to be explored. New discoveries related to osteocalcin function will assist its potential clinical application and physiological theory, but comprehensive investigations are required.
Collapse
Affiliation(s)
- Jinqiao Li
- China Astronaut Research and Training Center, State Key Lab of Space Medicine Fundamentals and Application, P.O.Box 1053-23#, No. 26, Beijing Road, Haidian District, Beijing, 100094, China
| | - Hongyu Zhang
- China Astronaut Research and Training Center, State Key Lab of Space Medicine Fundamentals and Application, P.O.Box 1053-23#, No. 26, Beijing Road, Haidian District, Beijing, 100094, China
| | - Chao Yang
- China Astronaut Research and Training Center, State Key Lab of Space Medicine Fundamentals and Application, P.O.Box 1053-23#, No. 26, Beijing Road, Haidian District, Beijing, 100094, China
| | - Yinghui Li
- China Astronaut Research and Training Center, State Key Lab of Space Medicine Fundamentals and Application, P.O.Box 1053-23#, No. 26, Beijing Road, Haidian District, Beijing, 100094, China
| | - Zhongquan Dai
- China Astronaut Research and Training Center, State Key Lab of Space Medicine Fundamentals and Application, P.O.Box 1053-23#, No. 26, Beijing Road, Haidian District, Beijing, 100094, China.
| |
Collapse
|
|
44
|
Wee N, Herzog H, Baldock P. 18. Diet-induced obesity alters skeletal microarchitecture and the endocrine activity of bone. HANDBOOK OF NUTRITION AND DIET IN THERAPY OF BONE DISEASES 2016. [DOI: 10.3920/978-90-8686-823-0_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- N.K.Y. Wee
- Bone Biology, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
| | - H. Herzog
- Neuroscience Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
| | - P.A. Baldock
- Bone Biology, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
| |
Collapse
|
|
45
|
Tascau L, Gardner T, Anan H, Yongpravat C, Cardozo CP, Bauman WA, Lee FY, Oh DS, Tawfeek HA. Activation of Protein Kinase A in Mature Osteoblasts Promotes a Major Bone Anabolic Response. Endocrinology 2016; 157:112-26. [PMID: 26488807 DOI: 10.1210/en.2015-1614] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Protein kinase A (PKA) regulates osteoblast cell function in vitro and is activated by important bone mass modulating agents. We determined whether PKA activation in osteoblasts is sufficient to mediate a bone anabolic response. Thus, a mouse model conditionally expressing a constitutively active PKA (CA-PKA) in osteoblasts (CA-PKA-OB mouse) was developed by crossing a 2.3-kb α1 (I)-collagen promoter-Cre mouse with a floxed-CA-PKA mouse. Primary osteoblasts from the CA-PKA-OB mice exhibited higher basal PKA activity than those from control mice. Microcomputed tomographic analysis revealed that CA-PKA-OB female mice had an 8.6-fold increase in femoral but only 1.16-fold increase in lumbar 5 vertebral bone volume/total volume. Femur cortical thickness and volume were also higher in the CA-PKA-OB mice. In contrast, alterations in many femoral microcomputed tomographic parameters in male CA-PKA-OB mice were modest. Interestingly, the 3-dimensional structure model index was substantially lower both in femur and lumbar 5 of male and female CA-PKA-OB mice, reflecting an increase in the plate to rod-like structure ratio. In agreement, femurs from female CA-PKA-OB mice had greater load to failure and were stiffer compared with those of control mice. Furthermore, the CA-PKA-OB mice had higher levels of serum bone turnover markers and increased osteoblast and osteoclast numbers per total tissue area compared with control animals. In summary, constitutive activation of PKA in osteoblasts is sufficient to increase bone mass and favorably modify bone architecture and improve mechanical properties. PKA activation in mature osteoblasts is, therefore, an important target for designing anabolic drugs for treating diseases with bone loss.
Collapse
Affiliation(s)
- Liana Tascau
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| | - Thomas Gardner
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| | - Hussein Anan
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| | - Charlie Yongpravat
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| | - Christopher P Cardozo
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| | - William A Bauman
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| | - Francis Y Lee
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| | - Daniel S Oh
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| | - Hesham A Tawfeek
- National Center for the Medical Consequences of Spinal Cord Injury (C.P.C., W.A.B., H.A.T.), James J. Peters VA Medical Center, Bronx, New York 10468; Center for Orthopaedic Research (T.G., C.Y., F.Y.L.), College of Dental Medicine (D.S.O.), and Department of Molecular Medicine (L.T.), Columbia University, and Departments of Medicine (C.P.C., W.A.B., H.A.T.), Rehabilitation Medicine (C.P.C., W.A.B.), and Pharmacology and Systems Therapeutics (C.P.C.), The Icahn School of Medicine at Mount Sinai, New York, New York 10029; and Sacred Heart Hospital/Temple University (H.A.), Allentown, Pennsylvania 16102
| |
Collapse
|
|
46
|
Balmayor ER. Targeted delivery as key for the success of small osteoinductive molecules. Adv Drug Deliv Rev 2015; 94:13-27. [PMID: 25959428 DOI: 10.1016/j.addr.2015.04.022] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 04/20/2015] [Accepted: 04/29/2015] [Indexed: 02/08/2023]
Abstract
Molecules such as growth factors, peptides and small molecules can guide cellular behavior and are thus important for tissue engineering. They are rapidly emerging as promising compounds for the regeneration of tissues of the musculoskeletal system. Growth factors have disadvantages such as high cost, short half-life, supraphysiological amounts needed, etc. Therefore, small molecules may be an alternative. These molecules have been discovered using high throughput screening. Small osteoinductive molecules exhibit several advantages over growth factors owing to their small sizes, such as high stability and non-immunogenicity. These molecules may stimulate directly signaling pathways that are important for osteogenesis. However, systemic application doesn't induce osteogenesis in most cases. Therefore, local administration is needed. This may be achieved by using a bone graft material providing additional osteoconductive properties. These graft materials can also act by themselves as a delivery matrix for targeted and local delivery. Furthermore, vascularization is necessary in the process of osteogenesis. Many of the small molecules are also capable of promoting vascularization of the tissue to be regenerated. Thus, in this review, special attention is given to molecules that are capable of inducing both angiogenesis and osteogenesis simultaneously. Finally, more recent preclinical and clinical uses in bone regeneration of those molecules are described, highlighting the needs for the clinical translation of these promising compounds.
Collapse
|
|
47
|
Koide H, Holmbeck K, Lui JC, Guo XC, Driggers P, Chu T, Tatsuno I, Quaglieri C, Kino T, Baron J, Young MF, Robey PG, Segars JH. Mice Deficient in AKAP13 (BRX) Are Osteoporotic and Have Impaired Osteogenesis. J Bone Miner Res 2015; 30:1887-95. [PMID: 25892096 PMCID: PMC4590282 DOI: 10.1002/jbmr.2534] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 04/03/2015] [Accepted: 04/15/2015] [Indexed: 01/23/2023]
Abstract
Mechanical stimulation is crucial to bone growth and triggers osteogenic differentiation through a process involving Rho and protein kinase A. We previously cloned a gene (AKAP13, aka BRX) encoding a protein kinase A-anchoring protein in the N-terminus, a guanine nucleotide-exchange factor for RhoA in the mid-section, coupled to a carboxyl region that binds to estrogen and glucocorticoid nuclear receptors. Because of the critical role of Rho, estrogen, and glucocorticoids in bone remodeling, we examined the multifunctional role of Akap13. Akap13 was expressed in bone, and mice haploinsufficient for Akap13 (Akap13(+/-)) displayed reduced bone mineral density, reduced bone volume/total volume, and trabecular number, and increased trabecular spacing; resembling the changes observed in osteoporotic bone. Consistent with the osteoporotic phenotype, Colony forming unit-fibroblast numbers were diminished in Akap13(+/-) mice, as were osteoblast numbers and extracellular matrix production when compared to control littermates. Transcripts of Runx2, an essential transcription factor for the osteogenic lineage, and alkaline phosphatase (Alp), an indicator of osteogenic commitment, were both reduced in femora of Akap13(+/-) mice. Knockdown of Akap13 reduced levels of Runx2 and Alp transcripts in immortalized bone marrow stem cells. These findings suggest that Akap13 haploinsufficient mice have a deficiency in early osteogenesis with a corresponding reduction in osteoblast number, but no impairment of mature osteoblast activity.
Collapse
Affiliation(s)
- Hisashi Koide
- Unit of Reproductive Endocrinology, Program in Reproductive and Adult Endocrinology (PRAE), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Kenn Holmbeck
- Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Julian C Lui
- Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Xiaoxiao C Guo
- Unit of Reproductive Endocrinology, Program in Reproductive and Adult Endocrinology (PRAE), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Paul Driggers
- Unit of Reproductive Endocrinology, Program in Reproductive and Adult Endocrinology (PRAE), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Tiffany Chu
- Unit of Reproductive Endocrinology, Program in Reproductive and Adult Endocrinology (PRAE), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Ichiro Tatsuno
- Center for Diabetes, Metabolism and Endocrinology, Toho University Sakura Medical Center, Chiba, Japan
| | - Caroline Quaglieri
- Unit of Reproductive Endocrinology, Program in Reproductive and Adult Endocrinology (PRAE), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Tomoshige Kino
- Unit of Reproductive Endocrinology, Program in Reproductive and Adult Endocrinology (PRAE), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Jeffrey Baron
- Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Marian F Young
- Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Pamela G Robey
- Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD, USA
| | - James H Segars
- Unit of Reproductive Endocrinology, Program in Reproductive and Adult Endocrinology (PRAE), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA
| |
Collapse
|
|
48
|
Xing J, Lian M, Shen Q, Feng G, Huang D, Lu X, Gu Z, Li L, Zhang J, Huang S, You Q, Wu X, Zhang D, Feng X. AGS3 is involved in TNF-α medicated osteogenic differentiation of human dental pulp stem cells. Differentiation 2015; 89:128-36. [DOI: 10.1016/j.diff.2015.06.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 05/27/2015] [Accepted: 06/17/2015] [Indexed: 01/01/2023]
|
|
49
|
Davies SG, Kennewell PD, Russell AJ, Seden PT, Westwood R, Wynne GM. Stemistry: the control of stem cells in situ using chemistry. J Med Chem 2015; 58:2863-94. [PMID: 25590360 DOI: 10.1021/jm500838d] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A new paradigm for drug research has emerged, namely the deliberate search for molecules able to selectively affect the proliferation, differentiation, and migration of adult stem cells within the tissues in which they exist. Recently, there has been significant interest in medicinal chemistry toward the discovery and design of low molecular weight molecules that affect stem cells and thus have novel therapeutic activity. We believe that a successful agent from such a discover program would have profound effects on the treatment of many long-term degenerative disorders. Among these conditions are examples such as cardiovascular decay, neurological disorders including Alzheimer's disease, and macular degeneration, all of which have significant unmet medical needs. This perspective will review evidence from the literature that indicates that discovery of such agents is achievable and represents a worthwhile pursuit for the skills of the medicinal chemist.
Collapse
Affiliation(s)
- Stephen G Davies
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| | - Peter D Kennewell
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| | - Angela J Russell
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K.,‡Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, U.K
| | - Peter T Seden
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| | - Robert Westwood
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| | - Graham M Wynne
- †Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K
| |
Collapse
|
|
50
|
Geng X, Xu T, Niu Z, Zhou X, Zhao L, Xie Z, Xue D, Zhang F, Xu C. Differential proteome analysis of the cell differentiation regulated by BCC, CRH, CXCR4, GnRH, GPCR, IL1 signaling pathways in Chinese fire-bellied newt limb regeneration. Differentiation 2014; 88:85-96. [DOI: 10.1016/j.diff.2014.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 10/07/2014] [Accepted: 10/29/2014] [Indexed: 12/11/2022]
|