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Stewart I, Garcia MJ, Alluri N, Buzo M, Keko M, Nazarian A. A Meta-Analysis Study to Define Variations in Murine Long Bone Biomechanical Testing. J Biomech Eng 2025; 147:060801. [PMID: 40172045 DOI: 10.1115/1.4068318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 03/13/2025] [Indexed: 04/04/2025]
Abstract
A systematic literature search and meta-analysis were performed to evaluate the variability in biomechanical testing of murine long bones, specifically focused on point-bending tests of mice femora. Due to the lack of standardized protocols for these tests, the assessment quantifies the heterogeneity in reported mechanical properties across existing literature. This study followed preferred reporting items for systematic reviews and meta-analyses (PRISMA) and strengthening the reporting of observational studies in epidemiology (STROBE) guidelines to search publicly available databases for relevant studies. After title and abstract screening, full-text reviews identified 73 articles meeting the inclusion criteria. Data was extracted from these studies, including stiffness, maximum load, modulus, and ultimate stress values for both three-point and four-point bending tests. The data were analyzed through ANOVA and metaregression to assess variability caused by age, sex, and genetic strain. The reviewers also assessed the quality of the included studies. The meta-analysis revealed significant heterogeneity in reported mechanical properties, with I2 values ranging from 72% to 100% in the three point-bend tests of pooled genetic strains. This heterogeneity persisted even after accounting for age, sex, and genetic strain differences. The review concludes that nonstandardized testing setups are the likely major source of the observed variability in reported data more than the population characteristics of the mice, highlighting the need for more consistent testing methodologies in future studies.
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Affiliation(s)
- Isabella Stewart
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215
- Beth Israel Deaconess Medical Center
| | - Mason J Garcia
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215; Department of Mechanical Engineering, Boston University, 330 Brookline Avenue, RN123, Boston, MA 02215
- Beth Israel Deaconess Medical Center
| | - Namitha Alluri
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215
- Beth Israel Deaconess Medical Center
| | - Maria Buzo
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215
- Beth Israel Deaconess Medical Center
| | - Mario Keko
- Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215
- Beth Israel Deaconess Medical Center
| | - Ara Nazarian
- Musculoskeletal Translational Innovation Initiative, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN123, Boston, MA 02215; Department of Mechanical Engineering, Boston University, Boston, MA 02215; Carl J. Shapiro Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Department of Orthopaedic Surgery, Yerevan State Medical University, Yerevan 0025, Armenia
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2
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Liu M, Liu C, Cevallos N, Orbach BN, Hernandez CJ, Fu X, Lee J, Booth SL, Shea MK. Dietary menaquinone-9 supplementation does not influence bone tissue quality or bone mineral density during skeletal development in mice. JBMR Plus 2025; 9:ziaf059. [PMID: 40386291 PMCID: PMC12083984 DOI: 10.1093/jbmrpl/ziaf059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/21/2025] [Accepted: 04/07/2025] [Indexed: 05/28/2025] Open
Abstract
Vitamin K has been implicated in skeletal health because vitamin K-dependent proteins are present in bone tissue. While there are multiple forms of vitamin K, most research has focused on phylloquinone, which is found mainly in plant-based foods, and its metabolite menaquinone-4 (MK4). However, there are additional forms of vitamin K that are bacterially produced that appear to influence bone health but have not yet been studied extensively. Herein, we evaluated the effects of menaquinone-9 (MK9), a bacterially produced form of vitamin K, on bone tissue quality and density in young mice. Four-week-old male (n = 32) and female (n = 32) C57BL/6 mice were supplemented with 0.06 mg/kg diet or 2.1 mg/kg diet of MK9 for 12 wk. During week 11, a subgroup of mice (n = 7/sex/group) received daily deuterium-labeled MK9 to trace its metabolic fate in bone. Liver MK4 and MK9 were significantly higher in mice fed 2.1 mg MK9/kg compared to those receiving 0.06 mg MK9/kg, regardless of sex (all p ≤ .017). MK4 was the only vitamin K form detected in bone, with 63%-67% of skeletal MK4 in mice fed 2.1 mg MK9/kg derived from deuterium-labeled MK9. Femoral tissue strength, maximum bending moment, section modulus, and BMD did not differ significantly between diet groups in either sex (all p ≥ .083). Cross-sectional area (p = .003) and moment of inertia (p = .001) were lower in female mice receiving 2.1 mg MK9/kg compared to those receiving 0.06 mg MK9/kg, but no differences were found in male mice. Higher bone MK4 concentrations did not correlate with higher bone tissue quality or density. Despite dietary MK9 being a dietary precursor to MK4 in bone, dietary MK9 supplementation did not affect bone tissue quality or BMD during skeletal development.
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Affiliation(s)
- Minying Liu
- USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States
| | - Chongshan Liu
- Orthopaedic Surgery, University of California, San Francisco, CA 94143, United States
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14850, United States
| | - Nicolas Cevallos
- Orthopaedic Surgery, University of California, San Francisco, CA 94143, United States
| | - Benjamin N Orbach
- USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States
| | | | - Xueyan Fu
- USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States
| | - Jennifer Lee
- USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, United States
| | - Sarah L Booth
- USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States
| | - M Kyla Shea
- USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States
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3
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Kirk B, Lombardi G, Duque G. Bone and muscle crosstalk in ageing and disease. Nat Rev Endocrinol 2025; 21:375-390. [PMID: 40011751 DOI: 10.1038/s41574-025-01088-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/30/2025] [Indexed: 02/28/2025]
Abstract
Interorgan communication between bone and skeletal muscle is central to human health. A dysregulation of bone-muscle crosstalk is implicated in several age-related diseases. Ageing-associated changes in endocrine, inflammatory, nutritional and biomechanical stimuli can influence the differentiation capacity, function and survival of mesenchymal stem cells and bone-forming and muscle-forming cells. Consequently, the secretome phenotype of bone and muscle cells is altered, leading to impaired crosstalk and, ultimately, catabolism of both tissues. Adipose tissue acts as a third player in the bone-muscle interaction by secreting factors that affect bone and muscle cells. Physical exercise remains the key biological stimulus for bone-muscle crosstalk, either directly via the release of cytokines from bone, muscle or adipocytes, or indirectly through extracellular vesicles. Overall, bone-muscle crosstalk is considered an inherent process necessary to maintain the structure and function of both tissues across the life cycle. This Review summarizes the latest biomedical advances in bone-muscle crosstalk as it pertains to human ageing and disease. We also outline future research priorities to accommodate the understanding of this rapidly emerging field.
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Affiliation(s)
- Ben Kirk
- Department of Medicine, Western Health, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, Melbourne, Victoria, Australia
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Advanced Diagnostics, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milan, Italy
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
| | - Gustavo Duque
- Department of Medicine, Western Health, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia.
- Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, Melbourne, Victoria, Australia.
- Bone, Muscle & Geroscience Group, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
- Dr. Joseph Kaufmann Chair in Geriatric Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada.
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4
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Risi R, Amendolara R, Balena A, Watanabe M, Masi D, Fassino V, Luverà D, D'Onofrio L, Lauria A, Zampetti S, Gnessi L, Maddaloni E, Buzzetti R. Osteocalcin is inversely associated with worse adipose tissue distribution and cardiovascular risk in autoimmune diabetes. Diabetes Res Clin Pract 2025; 223:112114. [PMID: 40139321 DOI: 10.1016/j.diabres.2025.112114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/18/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Osteocalcin (OCN), whose release is impaired in diabetes, is suggested to regulate the adipose tissue (AT), being potentially associated with Cardiovascular risk (CVR). We aimed at evaluating whether OCN serum levels are associated with AT health and CVR in a primary CV prevention population with AD. METHODS Body mass composition was assessed in sixty-two people with AD.Serum levels of OCN, adipokines and markers of endothelial dysfunction were measured. Regression models were used to test the association of OCN with markers of AT, endothelial dysfunction and CVR categories as determined by the Steno Type 1 Risk Engine (ST1RE) score. RESULTS OCN was inversely associated with upper body fat deposition index (UBDFI) (Adj β coefficient -0.484, p value = 0.001). People in medium/high CV risk categories had higher UBFDI and lower OCN, while biomarkers of endothelial dysfunction were not different across CVR classes. A logistic binary regression for ST1RE score showed significant association of OCN with medium/high CVR category: OR [95 % CI for 1 SD increase: 0.541 [0.264--1.108], p = 0.093]. CONCLUSION OCN is inversely associated with unhealthy AT, supporting the protective role of OCN in AT. Moreover, lower OCN levels are associated with increased CVR in AD population.
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Affiliation(s)
- Renata Risi
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Rocco Amendolara
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Angela Balena
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Mikiko Watanabe
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Davide Masi
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Valeria Fassino
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Daniela Luverà
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Luca D'Onofrio
- Department of Molecular Medicine, Sapienza University of Rome, Italy
| | - Angelo Lauria
- Diabetology Unit, San Camillo Forlanini Hospital, Rome, Italy
| | - Simona Zampetti
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Lucio Gnessi
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Ernesto Maddaloni
- Department of Experimental Medicine, Sapienza University of Rome, Italy.
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He T, Qin L, Chen S, Huo S, Li J, Zhang F, Yi W, Mei Y, Xiao G. Bone-derived factors mediate crosstalk between skeletal and extra-skeletal organs. Bone Res 2025; 13:49. [PMID: 40307216 PMCID: PMC12044029 DOI: 10.1038/s41413-025-00424-1] [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: 10/28/2024] [Revised: 03/15/2025] [Accepted: 03/20/2025] [Indexed: 05/02/2025] Open
Abstract
Bone has long been acknowledged as a fundamental structural entity that provides support and protection to the body's organs. However, emerging research indicates that bone plays a crucial role in the regulation of systemic metabolism. This is achieved through the secretion of a variety of hormones, cytokines, metal ions, extracellular vesicles, and other proteins/peptides, collectively referred to as bone-derived factors (BDFs). BDFs act as a medium through which bones can exert targeted regulatory functions upon various organs, thereby underscoring the profound and concrete implications of bone in human physiology. Nevertheless, there remains a pressing need for further investigations to elucidate the underlying mechanisms that inform the effects of bone on other body systems. This review aims to summarize the current findings related to the roles of these significant modulators across different organs and metabolic contexts by regulating critical genes and signaling pathways in vivo. It also addresses their involvement in the pathogenesis of various diseases affecting the musculoskeletal system, circulatory system, glucose and lipid metabolism, central nervous system, urinary system, and reproductive system. The insights gained from this review may contribute to the development of innovative therapeutic strategies through a focused approach to bone secretomes. Continued research into BDFs is expected to enhance our understanding of bone as a multifunctional organ with diverse regulatory roles in human health.
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Affiliation(s)
- Tailin He
- Department of Rheumatology and Immunology, Shenzhen Third People's Hospital, Shenzhen, 518112, China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), 100101, Beijing, China
- Department of Biochemistry, Homeostatic Medicine Institute, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Lei Qin
- Department of Orthopedics, Shenzhen Nanshan People's Hospital, and the 6th Affiliated Hospital of Shenzhen University Medical School, Shenzhen, 518052, China
| | - Sheng Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shaochuan Huo
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen 518000, China, Shenzhen Research Institute of Guangzhou University of Traditional Medicine (Futian), Shenzhen, 518000, China
| | - Jie Li
- Department of Biochemistry, Homeostatic Medicine Institute, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Fuping Zhang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), 100101, Beijing, China
| | - Weihong Yi
- Department of Orthopedics, Shenzhen Nanshan People's Hospital, and the 6th Affiliated Hospital of Shenzhen University Medical School, Shenzhen, 518052, China
| | - Yifang Mei
- Department of Rheumatology and Immunology, Shenzhen Third People's Hospital, Shenzhen, 518112, China.
| | - Guozhi Xiao
- Department of Biochemistry, Homeostatic Medicine Institute, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, 518055, China.
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6
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Liu M, Liu C, Cevallos N, Orbach BN, Hernandez CJ, Fu X, Lee J, Booth SL, Shea MK. Dietary Menaquinone-9 Supplementation Does Not Influence Bone Tissue Quality or Bone Mineral Density in Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.29.635567. [PMID: 39975193 PMCID: PMC11838345 DOI: 10.1101/2025.01.29.635567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Vitamin K has been implicated in skeletal health because vitamin K-dependent proteins are present in bone. While there are multiple forms of vitamin K, most research has focused on phylloquinone, which is found mainly in plant-based foods, and its metabolite menaquinone-4 (MK4). However, there are additional forms of vitamin K that are bacterially produced that appear to influence bone health but have not yet been studied extensively. Herein, we evaluated the effects of menaquinone-9 (MK9), a bacterially produced form of vitamin K on bone tissue quality and density in young mice. Four-week-old male (n=32) and female (n=32) C57BL/6 mice were supplemented with 0.06 mg/kg diet or 2.1 mg/kg diet of MK9 for 12 weeks. During week 11, a sub-group of mice (n=7/sex/group) received daily deuterium-labeled MK9 to trace its metabolic fate in bone. Liver MK4 and MK9 were significantly higher in mice fed 2.1 mg MK9/kg compared to those receiving 0.06 mg MK9/kg, regardless of sex (all p ≤ 0.017). MK4 was the only vitamin K form detected in bone, with 63-67% of skeletal MK4 in mice fed 2.1 mg MK9/kg derived from deuterium-labeled MK9. Femoral tissue strength, maximum bending moment, section modulus, and bone mineral density did not differ significantly across diet groups in either sex (all p≥0.083). Cross-sectional area (p=0.003) and moment of inertia (p=0.001) were lower in female mice receiving 2.1 mg MK9/kg compared to those receiving 0.06 mg MK9/kg, but no differences were found in male mice. Higher bone MK4 concentrations did not correlate with higher bone tissue quality or density. Despite dietary MK9 being a dietary precursor to MK4 in bone, dietary MK9 supplementation did not affect bone tissue quality or bone mineral density.
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Affiliation(s)
- Minying Liu
- Human Nutrition Research Center on Aging, Tufts University, Boston, MA
| | - Chongshan Liu
- Orthopaedic Surgery, University of California, San Francisco, CA
- Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY
| | - Nicolas Cevallos
- Orthopaedic Surgery, University of California, San Francisco, CA
| | - Benjamin N Orbach
- Human Nutrition Research Center on Aging, Tufts University, Boston, MA
| | | | - Xueyan Fu
- Human Nutrition Research Center on Aging, Tufts University, Boston, MA
| | - Jennifer Lee
- Human Nutrition Research Center on Aging, Tufts University, Boston, MA
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA
| | - Sarah L Booth
- Human Nutrition Research Center on Aging, Tufts University, Boston, MA
| | - M Kyla Shea
- Human Nutrition Research Center on Aging, Tufts University, Boston, MA
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7
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Komori T. Bone development by Hedgehog and Wnt signaling, Runx2, and Sp7. J Bone Miner Metab 2025; 43:33-38. [PMID: 39352550 DOI: 10.1007/s00774-024-01551-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 08/25/2024] [Indexed: 04/01/2025]
Abstract
Hedgehog and canonical Wnt signaling pathways and the transcription factors Runx2 and Sp7 are essential for osteoblast differentiation. Ihh is necessary for the commitment of perichondrial mesenchymal cells to Runx2+ osteoprogenitors and for the formation of the bone collar and primary spongiosa. Runx2 is needed for osteoblast differentiation during both endochondral and intramembranous ossification. It regulates the commitment of mesenchymal cells to osteoblast-lineage cells and their proliferation by inducing the expression of Hedgehog, Fgf, Wnt, Pthlh signaling pathway genes, and Dlx5. The Runx2-induced expression of Fgfr2 and Fgfr3 is important for the proliferation of osteoblast-lineage cells. Runx2 induces Sp7 expression and Runx2+ osteoprogenitors become Runx2+Sp7+ preosteoblasts. Runx2, Sp7, and canonical Wnt signaling induce the differentiation of preosteoblasts into osteoblasts. Canonical Wnt signaling, but not Sp7, enhances the proliferation of osteoblast-lineage cells. In mature osteoblasts, Runx2 plays an important role in the expression of major bone matrix protein genes, including Col1a1, Col1a2, Spp1, Ibsp, and Bglap/Bglap2. The canonical Wnt signaling pathway is also crucial for bone formation by mature osteoblasts. Sp7 is needed for osteocytes to acquire a sufficient number of processes and a reduction in these processes results in osteocyte apoptosis and cortical porosity.
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Affiliation(s)
- Toshihisa Komori
- Department of Molecular Tumor Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.
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8
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Taib IS, Jayusman PA. The Role of Bone-Derived Osteocalcin in Testicular Steroidogenesis: Contributing Factor to Male Fertility. Diseases 2024; 12:335. [PMID: 39727665 PMCID: PMC11727589 DOI: 10.3390/diseases12120335] [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: 10/11/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 12/28/2024] Open
Abstract
Osteocalcin (OCN), a protein predominantly produced by osteoblasts in bone, has emerged as a significant factor in bone metabolism and reproductive function. This article reviews the latest research on the role of OCN beyond its traditional functions in bone mineralisation, particularly its influence on testicular steroidogenesis and male fertility. The structure and modifications of OCN are elaborated upon, highlighting its uncarboxylated form (ucOCN), which is becoming increasingly recognised for its bioactive properties. The impact of OCN on bone quantity, quality and strength is summarised, emphasising its role as a regulator of bone metabolism. Furthermore, the influence of ucOCN on testicular steroidogenesis and the involvement of GPRC6A, a G protein-coupled receptor, in mediating these effects are also explored. Evidence suggests that ucOCN regulates testosterone synthesis and spermatogenesis, which indirectly have the potential to influence bone metabolism integrity. In conclusion, OCN, particularly in its uncarboxylated form, plays a crucial role in bone metabolism and male fertility by regulating testicular steroidogenesis, with GPRC6A mediating these effects, thereby linking bone health and reproductive functions.
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Affiliation(s)
- Izatus Shima Taib
- Centre of Diagnostics, Therapeutics and Investigative Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia;
| | - Putri Ayu Jayusman
- Department of Craniofacial Diagnostics and Biosciences, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia
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9
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Carlomagno F, Hasenmajer V, Spaziani M, Tenuta M, Sesti F, Tarantino C, Pozza C, Isidori AM, Gianfrilli D. Total osteocalcin levels are independently associated with worse testicular function and a higher degree of hypothalamic-pituitary-gonadal axis activation in Klinefelter syndrome. J Endocrinol Invest 2024; 47:3049-3056. [PMID: 38773059 PMCID: PMC11549210 DOI: 10.1007/s40618-024-02390-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 05/02/2024] [Indexed: 05/23/2024]
Abstract
PURPOSE The role of osteocalcin (OCN) in pubertal development, male hypogonadism, and the effect of testosterone (Te) replacement therapy (TRT) remains unclear. We aimed to investigate the total OCN (tOCN) concentrations in male patients with Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism. METHODS This retrospective longitudinal study investigated 254 male patients with KS (47,XXY) between 2007 and 2021 at an academic referral center, categorized as (1) prepubertal, (2) pubertal, and (3) adults. All prepubertal patients were Te-naïve. Adult patients were subcategorized as (1) eugonadal, (2) hypogonadal, and (3) receiving TRT. We also analyzed 18 adult patients with available tOCN levels before and 3 months after TRT commencement. RESULTS The tOCN levels varied throughout the lifespan according to pubertal status, were highest in eugonadal and significantly lower in TRT subjects, correlated with both LH (p = 0.017) and FSH levels (p = 0.004) in adults, and significantly declined after 3 months of TRT (p = 0.006) in the adult KS cohort. HPG-axis hormones levels demonstrated no correlation in prepubertal boys. Adjustment for age and body mass index confirmed previous results and revealed significant inverse correlations with total Te (p = 0.004), calculated free Te (p = 0.016), the Te/LH (p = 0.010), and calculated free Te/LH ratios (p = 0.031). CONCLUSION In KS, a model of male hypergonadotropic hypogonadism, tOCN levels were not associated with gonadal function during normal prepuberty and pubertal development but were associated with worse testicular function and a higher degree of HPG stimulation in adults. TRT acutely reduced tOCN levels in adults.
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Affiliation(s)
- F Carlomagno
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - V Hasenmajer
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - M Spaziani
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - M Tenuta
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - F Sesti
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - C Tarantino
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - C Pozza
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - A M Isidori
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy
- Endocrine and Andrological Regional Rare Disease Center (Endo-ERN Accredited), Policlinico Umberto I, 00161, Rome, Italy
| | - D Gianfrilli
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy.
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10
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Bernhard M, Okorie O, Tseng WJ, Chen M, Danon J, Cui M, Lashbrooks E, Yang Y, Wang B. Metabolic shifts in ratio of ucOcn to cOcn toward bone resorption contribute to age-dependent bone loss in male mice. Am J Physiol Endocrinol Metab 2024; 327:E711-E722. [PMID: 39441240 PMCID: PMC11684868 DOI: 10.1152/ajpendo.00294.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/24/2024] [Accepted: 10/08/2024] [Indexed: 10/25/2024]
Abstract
The study of the senile osteoporosis in men still lags significantly behind that in women. The changes of protein molecule levels and their relationships with bone loss remain poorly understood. In the present study, we used C57BL/6J male mice at ages from 3 to 24 mo to delineate the mechanisms of aging effects on bone loss. We used the microcomputed tomography, mechanical testing, histomorphometry assays, and detection of serum levels of undercarboxylated osteocalcin (ucOcn) and carboxylated osteocalcin (cOcn) to assess bone mass changes and their relationships with the ratios of ucOcn-to-cOcn in mice from different age groups. The results showed that mouse trabecular bone mass reduced gradually with age, whereas cortical bone loss and mechanical property changes mostly occurred in advanced age. Our findings further demonstrated that the increase in osteoclast activity and the decrease in osteoblast function were significantly corelated with blood levels of ucOcn and cOcn, respectively. The dynamic metabolic changes of ucOcn to cOcn ratio were correlated with age-dependent bone loss in mice. In summary, metabolic shifts in the ratio of ucOcn to cOcn toward bone resorption from young adult to elderly mice contribute to the pathogenesis of age-related bone loss. Simultaneously monitoring blood ratios of ucOcn-to-cOcn may be useful to predict the status of bone mass in vivo.NEW & NOTEWORTHY To our knowledge, our finding in this study shows for the first time that metabolic shifts in ratio of ucOcn to cOcn toward bone resorption are markedly correlated with age-dependent bone loss in male mice. These findings for the effects of aging on bone loss will assist in studying the pathogenesis of human type II osteoporosis.
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Affiliation(s)
- Matthew Bernhard
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Obinna Okorie
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Wei-Ju Tseng
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Mengcun Chen
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Julia Danon
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Mingshu Cui
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Elisabeth Lashbrooks
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Yanmei Yang
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
| | - Bin Wang
- Departments of Medicine, The Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
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11
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Ronghe R, Tavares AAS. The skeleton: an overlooked regulator of systemic glucose metabolism in cancer? Front Oncol 2024; 14:1481241. [PMID: 39588310 PMCID: PMC11586348 DOI: 10.3389/fonc.2024.1481241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/22/2024] [Indexed: 11/27/2024] Open
Abstract
Recent discoveries demonstrated the skeleton's role as an endocrine organ regulating whole-body glucose homeostasis. Glucose metabolism is critical for rapid cell proliferation and tumour growth through increasing glucose uptake and fermentation of glucose to lactate despite being in an aerobic environment. This hypothesis paper discusses emerging evidence on how bones can regulate whole-body glucose homeostasis with potential to impact on tumour growth and proliferation. Moreover, it proposes a clinical link between bone glucose metabolism and prognosis of cancer based on recent clinical trial data. Targeting metabolic pathways related with classic glucose metabolism and also bone metabolism, novel methods of cancer therapy and treatment could be developed. This paper objective is to highlight the need for future research on this altered metabolism with potential to change future management of cancer patients.
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Affiliation(s)
- Rucha Ronghe
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, United Kingdom
| | - Adriana A. S. Tavares
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, United Kingdom
- Edinburgh Imaging, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, United Kingdom
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12
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Bessueille L, Briolay A, Guillot N, Mebarek S, Viallon S, Laroche N, Lafage-Proust MH, Magne D. Teriparatide administration is osteoanabolic but does not impact atherosclerotic plaque calcification and progression in a mouse model of menopause. Bone 2024; 190:117316. [PMID: 39491714 DOI: 10.1016/j.bone.2024.117316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/30/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
Menopause exacerbates osteoporosis and increases the risk of atherosclerotic plaque rupture, leading to cardiovascular mortality. Osteoporotic women are increasingly treated with teriparatide (TPTD, 1-34 parathyroid hormone), one of the few treatments that stimulate bone formation. Despite the fact that atherosclerotic plaque calcification is a hallmark of plaque development, the impact of TPTD administration on plaque calcification remain unclear. In this context, we sought to determine the effects of TPTD administration on atherosclerosis in ovariectomized (OVX) apolipoprotein E deficient mice (ApoE-/-), as a model of postmenopausal osteoporosis. OVX ApoE-/- mice, fed a high fat, high cholesterol diet to induce atherosclerosis, received either vehicle or TPTD daily injections (40 μg/kg/d) for 4 or 10 weeks, at which points plaques are respectively weakly and heavily calcified. After sacrifice, bone remodeling was evaluated by serum markers and bone histomorphometry. Bone architectural parameters were measured by μCT. Aortic plaques were analyzed histologically, and their calcification with von Kossa staining and the calcium tracer Osteosense. Plaque inflammation and calcification markers were measured by RT-qPCR. Intermittent TPTD increased bone volume in OVX mice, due to a higher stimulation of bone formation relatively to bone resorption. These effects were not accompanied by changes in serum levels of cholesterol, triglycerides, glucose or insulin. TPTD neither significantly affected aortic plaque size, inflammation, and calcification, even if it slightly increased vascular smooth muscle cell transdifferentiation into calcifying cells. In conclusion, TPTD exhibits osteoanabolic effects in OVX ApoE-/- mice, without significantly influencing atherosclerotic plaque progression or calcification in the short term.
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Affiliation(s)
- Laurence Bessueille
- Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5246, ICBMS, F69622 Lyon, France
| | - Anne Briolay
- Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5246, ICBMS, F69622 Lyon, France
| | - Nicolas Guillot
- Université Claude Bernard Lyon 1, Laboratoire Interuniversitaire de Biologie de la Motricité (LiBM) EA7424, Team Vascular Biology and Red Blood Cell, F69622 Villeurbanne, France
| | - Saïda Mebarek
- Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5246, ICBMS, F69622 Lyon, France
| | - Solène Viallon
- Université Jean Monnet Saint-Étienne, Mines Saint-Étienne, INSERM, SAINBIOSE U1059, F42023 Saint-Étienne, France
| | - Norbert Laroche
- Université Jean Monnet Saint-Étienne, Mines Saint-Étienne, INSERM, SAINBIOSE U1059, F42023 Saint-Étienne, France
| | - Marie-Hélène Lafage-Proust
- Université Jean Monnet Saint-Étienne, Mines Saint-Étienne, INSERM, SAINBIOSE U1059, F42023 Saint-Étienne, France
| | - David Magne
- Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5246, ICBMS, F69622 Lyon, France.
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13
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Song F, Marmo T, Song C, Liao X, Long F. Wnt7b overexpression in osteoblasts stimulates bone formation and reduces obesity in mice on a high-fat diet. JBMR Plus 2024; 8:ziae122. [PMID: 39434845 PMCID: PMC11491285 DOI: 10.1093/jbmrpl/ziae122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/04/2024] [Accepted: 09/17/2024] [Indexed: 10/23/2024] Open
Abstract
Previous studies have shown that Wnt7b potently stimulates bone formation by promoting osteoblast differentiation and activity. As high-fat feeding leads to obesity and systemic metabolic dysregulation, here we investigate the potential benefit of Wnt7b overexpression in osteoblasts on both bone and whole-body metabolism in mice fed with a high-fat diet (HFD). Wnt7b overexpression elicited massive overgrowth of trabecular and cortical bone but seemed to ameliorate body fat accumulation in mice with prolonged HFD feeding. In addition, Wnt7b overexpression modestly improved glucose tolerance in male mice on HFD. Collectively, the results indicate that targeted overexpression of Wnt7b in osteoblasts not only stimulates bone formation but also improves certain aspects of global metabolism in overnourished mice.
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Affiliation(s)
- Fangfang Song
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China
- Translational Research Program in Pediatric Orthopedics, Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
| | - Tyler Marmo
- Translational Research Program in Pediatric Orthopedics, Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
| | - Chao Song
- Translational Research Program in Pediatric Orthopedics, Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
| | - Xueyang Liao
- Translational Research Program in Pediatric Orthopedics, Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
| | - Fanxin Long
- Translational Research Program in Pediatric Orthopedics, Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
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14
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Smith C, Lin X, Parker L, Yeap BB, Hayes A, Levinger I. The role of bone in energy metabolism: A focus on osteocalcin. Bone 2024; 188:117238. [PMID: 39153587 DOI: 10.1016/j.bone.2024.117238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/06/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
Understanding the mechanisms involved in whole body glucose regulation is key for the discovery of new treatments for type 2 diabetes (T2D). Historically, glucose regulation was largely focused on responses to insulin and glucagon. Impacts of incretin-based therapies, and importance of muscle mass, are also highly relevant. Recently, bone was recognized as an endocrine organ, with several bone proteins, known as osteokines, implicated in glucose metabolism through their effects on the liver, skeletal muscle, and adipose tissue. Research efforts mostly focused on osteocalcin (OC) as a leading example. This review will provide an overview on this role of bone by discussing bone turnover markers (BTMs), the receptor activator of nuclear factor kB ligand (RANKL), osteoprotegerin (OPG), sclerostin (SCL) and lipocalin 2 (LCN2), with a focus on OC. Since 2007, some, but not all, research using mostly OC genetically modified animal models suggested undercarboxylated (uc) OC acts as a hormone involved in energy metabolism. Most data generated from in vivo, ex vivo and in vitro models, indicate that exogenous ucOC administration improves whole-body and skeletal muscle glucose metabolism. Although data in humans are generally supportive, findings are often discordant likely due to methodological differences and observational nature of that research. Overall, evidence supports the concept that bone-derived factors are involved in energy metabolism, some having beneficial effects (ucOC, OPG) others negative (RANKL, SCL), with the role of some (LCN2, other BTMs) remaining unclear. Whether the effect of osteokines on glucose regulation is clinically significant and of therapeutic value for people with insulin resistance and T2D remains to be confirmed.
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Affiliation(s)
- Cassandra Smith
- Nutrition & Health Innovation Research Institute, School of Health and Medical Sciences, Edith Cowan University, Perth, Western Australia, Australia; Medical School, The University of Western Australia, Perth, Western Australia, Australia; Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia
| | - Xuzhu Lin
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Lewan Parker
- Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, VIC, Australia
| | - Bu B Yeap
- Medical School, The University of Western Australia, Perth, Western Australia, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia
| | - Alan Hayes
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Footscray, VIC, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Footscray, VIC, Australia.
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15
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Komori T. Regulation of Skeletal Development and Maintenance by Runx2 and Sp7. Int J Mol Sci 2024; 25:10102. [PMID: 39337587 PMCID: PMC11432631 DOI: 10.3390/ijms251810102] [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: 07/29/2024] [Revised: 09/16/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Runx2 (runt related transcription factor 2) and Sp7 (Sp7 transcription factor 7) are crucial transcription factors for bone development. The cotranscription factor Cbfb (core binding factor beta), which enhances the DNA-binding capacity of Runx2 and stabilizes the Runx2 protein, is necessary for bone development. Runx2 is essential for chondrocyte maturation, and Sp7 is partly involved. Runx2 induces the commitment of multipotent mesenchymal cells to osteoblast lineage cells and enhances the proliferation of osteoprogenitors. Reciprocal regulation between Runx2 and the Hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathways and Dlx5 (distal-less homeobox 5) plays an important role in these processes. The induction of Fgfr2 (Fgf receptor 2) and Fgfr3 expression by Runx2 is important for the proliferation of osteoblast lineage cells. Runx2 induces Sp7 expression, and Runx2+ osteoprogenitors become Runx2+Sp7+ preosteoblasts. Sp7 induces the differentiation of preosteoblasts into osteoblasts without enhancing their proliferation. In osteoblasts, Runx2 is required for bone formation by inducing the expression of major bone matrix protein genes, including Col1a1 (collagen type I alpha 1), Col1a2, Spp1 (secreted phosphoprotein 1), Ibsp (integrin binding sialoprotein), and Bglap (bone gamma carboxyglutamate protein)/Bglap2. Bglap/Bglap2 (osteocalcin) regulates the alignment of apatite crystals parallel to collagen fibrils but does not function as a hormone that regulates glucose metabolism, testosterone synthesis, and muscle mass. Sp7 is also involved in Co1a1 expression and regulates osteoblast/osteocyte process formation, which is necessary for the survival of osteocytes and the prevention of cortical porosity. SP7 mutations cause osteogenesis imperfecta in rare cases. Runx2 is an important pathogenic factor, while Runx1, Runx3, and Cbfb are protective factors in osteoarthritis development.
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Affiliation(s)
- Toshihisa Komori
- Department of Molecular Tumor Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
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16
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Lafage-Proust MH, Magne D. Biology of bone mineralization and ectopic calcifications: the same actors for different plays. Arch Pediatr 2024; 31:4S3-4S12. [PMID: 39343471 DOI: 10.1016/s0929-693x(24)00151-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Bone has several crucial functions. It is essential for locomotion and allows our body to stand erect against gravity. A mismatch between the mechanical stresses applied to it and its mechanical resistance leads to fractures. Bone also has numerous endocrine functions. It acts as a reservoir for minerals such as calcium and phosphorus, making it the target of calciotropic hormones that mobilize these minerals, particularly calcium, according to the body's needs. Additionally, bone secretes hormones, notably fibroblast growth factor 23 (FGF23), which regulates urinary excretion of phosphate and the bioavailability of active vitamin D. Bone mineralization is the process that facilitates the organized deposition of minerals in the bone matrix, providing rigidity and appropriate mechanical resistance. This process is compromised in genetically related bone mineralization disorders, such as those causing hypophosphatemia or hypophosphatasia. Conversely, calcification can be pathological, affecting soft tissues like the blood vessels, as seen in generalized arterial calcification of infancy (GACI) or arterial calcification due to CD73 deficiency (ACDC). The aim of this article is to first present the composition and structure of the mineralized bone matrix, to review the current understanding of the molecular mechanisms of mineralization, and finally to discuss the conditions associated with ectopic calcification and the underlying mechanisms.
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Affiliation(s)
| | - David Magne
- University of Lyon I; ICBMS, UMR CNRS 5246, F-69622, LYON, France.
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17
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Lacombe J, Ferron M. Vitamin K-dependent carboxylation in β-cells and diabetes. Trends Endocrinol Metab 2024; 35:661-673. [PMID: 38429160 DOI: 10.1016/j.tem.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/05/2024] [Accepted: 02/07/2024] [Indexed: 03/03/2024]
Abstract
Vitamin K is an essential micronutrient and a cofactor for the enzyme γ-glutamyl carboxylase, which adds a carboxyl group to specific glutamic acid residues in proteins transiting through the secretory pathway. Higher vitamin K intake has been linked to a reduced incidence of type 2 diabetes (T2D) in humans. Preclinical work suggests that this effect depends on the γ-carboxylation of specific proteins in β-cells, including endoplasmic reticulum Gla protein (ERGP), implicated in the control of intracellular Ca2+ levels. In this review we discuss these recent advances linking vitamin K and glucose metabolism, and argue that identification of γ-carboxylated proteins in β-cells is pivotal to better understand how vitamin K protects from T2D and to design targeted therapies for this disease.
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Affiliation(s)
- Julie Lacombe
- Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7, Canada.
| | - Mathieu Ferron
- Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W 1R7, Canada; Programme de Biologie Moléculaire, Université de Montréal, Montréal, QC, H3T 1J4, Canada; Département de Médecine, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
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18
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Wang C, Fan M, Heo SJ, Adams SM, Li T, Liu Y, Li Q, Loebel C, Alisafaei F, Burdick JA, Lu XL, Birk DE, Mauck RL, Han L. Structure-Mechanics Principles and Mechanobiology of Fibrocartilage Pericellular Matrix: A Pivotal Role of Type V Collagen. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.26.600498. [PMID: 38979323 PMCID: PMC11230444 DOI: 10.1101/2024.06.26.600498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
The pericellular matrix (PCM) is the immediate microniche surrounding resident cells in various tissue types, regulating matrix turnover, cell-matrix cross-talk and disease initiation. This study elucidated the structure-mechanical properties and mechanobiological functions of the PCM in fibrocartilage, a family of connective tissues that sustain complex tensile and compressive loads in vivo. Studying the murine meniscus as the model tissue, we showed that fibrocartilage PCM contains thinner, random collagen fibrillar networks that entrap proteoglycans, a structure distinct from the densely packed, highly aligned collagen fibers in the bulk extracellular matrix (ECM). In comparison to the ECM, the PCM has a lower modulus and greater isotropy, but similar relative viscoelastic properties. In Col5a1 +/- menisci, the reduction of collagen V, a minor collagen localized in the PCM, resulted in aberrant fibril thickening with increased heterogeneity. Consequently, the PCM exhibited a reduced modulus, loss of isotropy and faster viscoelastic relaxation. This disrupted PCM contributes to perturbed mechanotransduction of resident meniscal cells, as illustrated by reduced intracellular calcium signaling, as well as upregulated biosynthesis of lysyl oxidase and tenascin C. When cultured in vitro, Col5a1 +/- meniscal cells synthesized a weakened nascent PCM, which had inferior properties towards protecting resident cells against applied tensile stretch. These findings underscore the PCM as a distinctive microstructure that governs fibrocartilage mechanobiology, and highlight the pivotal role of collagen V in PCM function. Targeting the PCM or its molecular constituents holds promise for enhancing not only meniscus regeneration and osteoarthritis intervention, but also addressing diseases across various fibrocartilaginous tissues.
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Affiliation(s)
- Chao Wang
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
| | - Mingyue Fan
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
| | - Su-Jin Heo
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Sheila M. Adams
- Department of Molecular Pharmacology and Physiology, Morsani School of Medicine, University of South Florida, Tampa, FL 33612, United States
| | - Thomas Li
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
| | - Yuchen Liu
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
| | - Qing Li
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
| | - Claudia Loebel
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Farid Alisafaei
- Department of Mechanical and Industrial Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States
| | - Jason A. Burdick
- BioFrontiers Institute and Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO 80309, United States
| | - X. Lucas Lu
- Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, United States
| | - David E. Birk
- Department of Molecular Pharmacology and Physiology, Morsani School of Medicine, University of South Florida, Tampa, FL 33612, United States
| | - Robert L. Mauck
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Veterans Administration Medical Center, Philadelphia, PA 19104, United States
| | - Lin Han
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
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19
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Nowicki JK, Jakubowska-Pietkiewicz E. Osteocalcin: Beyond Bones. Endocrinol Metab (Seoul) 2024; 39:399-406. [PMID: 38803289 PMCID: PMC11220208 DOI: 10.3803/enm.2023.1895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/23/2024] [Accepted: 01/31/2024] [Indexed: 05/29/2024] Open
Abstract
Apart from basic roles such as supporting the body, protecting internal organs, and storing calcium, the skeletal system also performs hormonal functions. In recent years, several reports have been published on proteins secreted by bones and their impact on the homeostasis of the entire body. These proteins include fibroblast growth factor 23, sclerostin, lipocalin 2, and osteocalcin. Osteocalcin, the most abundant non-collagenous protein in bone tissue, is routinely measured as a clinical marker for diagnosing bone metabolism disorders. Its molecule undergoes numerous transformations, with decarboxylation being the critical process. Decarboxylation occurs in the acidic environment typical of bone resorption, facilitating the release of the molecule into the bloodstream and enabling its hormonal action. Decarboxylated osteocalcin promotes insulin secretion and stimulates the proliferation of pancreatic islet β-cells. It also plays a role in reducing the accumulation of visceral fat and decreasing fat storage in the liver. Furthermore, decarboxylated osteocalcin levels are inversely correlated with fasting serum glucose levels, total body fat, visceral fat area, and body mass index. Apart from its role in energy metabolism, osteocalcin affects testosterone production and the synthesis of glucagon-like peptide-1. It is also actively involved in muscle-bone crosstalk and influences cognitive function.
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Affiliation(s)
- Jakub Krzysztof Nowicki
- Department of Pediatrics, Neonatal Pathology and Metabolic Bone Diseases, Medical University of Lodz, Lodz, Poland
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20
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Arakil N, Akhund SA, Elaasser B, Mohammad KS. Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis. Biomedicines 2024; 12:1075. [PMID: 38791037 PMCID: PMC11117796 DOI: 10.3390/biomedicines12051075] [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: 03/17/2024] [Revised: 04/27/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
The phenomenon of bone metastases presents a significant challenge within the context of advanced cancer treatments, particularly pertaining to breast, prostate, and lung cancers. These metastatic occurrences stem from the dissemination of cancerous cells into the bone, thereby interrupting the equilibrium between osteoblasts and osteoclasts. Such disruption results in skeletal complications, adversely affecting patient morbidity and quality of life. This review discusses the intricate interplay between cancer cells and the bone microenvironment, positing the bone not merely as a passive recipient of metastatic cells but as an active contributor to cancer progression through its distinctive biochemical and cellular makeup. A thorough examination of bone structure and the dynamics of bone remodeling is undertaken, elucidating how metastatic cancer cells exploit these processes. This review explores the genetic and molecular pathways that underpin the onset and development of bone metastases. Particular emphasis is placed on the roles of cytokines and growth factors in facilitating osteoclastogenesis and influencing osteoblast activity. Additionally, this paper offers a meticulous critique of current diagnostic methodologies, ranging from conventional radiography to advanced molecular imaging techniques, and discusses the implications of a nuanced understanding of bone metastasis biology for therapeutic intervention. This includes the development of targeted therapies and strategies for managing bone pain and other skeletal-related events. Moreover, this review underscores the imperative of ongoing research efforts aimed at identifying novel therapeutic targets and refining management approaches for bone metastases. It advocates for a multidisciplinary strategy that integrates advancements in medical oncology and radiology with insights derived from molecular biology and genetics, to enhance prognostic outcomes and the quality of life for patients afflicted by this debilitating condition. In summary, bone metastases constitute a complex issue that demands a comprehensive and informed approach to treatment. This article contributes to the ongoing discourse by consolidating existing knowledge and identifying avenues for future investigation, with the overarching objective of ameliorating patient care in the domain of oncology.
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Affiliation(s)
| | | | | | - Khalid S. Mohammad
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 1153, Saudi Arabia; (N.A.); (S.A.A.); (B.E.)
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21
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Paracha N, Mastrokostas P, Kello E, Gedailovich Y, Segall D, Rizzo A, Mitelberg L, Hassan N, Dowd TL. Osteocalcin improves glucose tolerance, insulin sensitivity and secretion in older male mice. Bone 2024; 182:117048. [PMID: 38378083 DOI: 10.1016/j.bone.2024.117048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 01/19/2024] [Accepted: 02/09/2024] [Indexed: 02/22/2024]
Abstract
Osteocalcin deficient mice (OC-/-), on a mixed 129/BL6J background, were reported to show glucose intolerance, insulin insensitivity and reduced insulin secretion at 1-6 mos of age. This is controversial as two studies in OC-/- mice on different backgrounds (C3H/BL6 (5-6 mos.) and C57BL/6N (5 and 9 mos.)) found no effect on glucose metabolism. To determine the role of OC in glucose metabolism we conducted glucose tolerance tests (GTT), insulin tolerances tests (ITT) and glucose stimulated insulin secretion (GSIS) on 6 and 9.5 month-old male OC-/- and OC+/+ mice on a pure C57BL/6J background and fed a normal chow diet. All results were analyzed with a two-way repeated measures ANOVA. The GTT results showed no effect on males at 6 months of age but glucose intolerance was significantly increased (p < 0.05) in male OC-/- mice at 9.5 months of age. The ITT results indicated significantly increased insulin resistance in male OC-/- mice. Glucose stimulated insulin secretion (GSIS) showed insulin significantly (p < 0.05) reduced in OC-/- at several time points. Mouse Osteocalcin injected into OC-/- mice decreased the glucose level. Our results confirm the role of OC in glucose metabolism and insulin sensitivity and demonstrate a role in insulin secretion in older male mice on a C57BL/6J background. Differences in background, age, or experimental procedures could explain controversial results. A delayed onset of the effect of OC on glucose metabolism at 9.5 months in male C57BL/6J mice highlights the importance of background on phenotype. Consideration of genetic background and age may be beneficial for human studies on osteocalcin and glucose homeostasis and may be relevant to the elderly where osteocalcin is reduced.
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Affiliation(s)
- Noorulain Paracha
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America
| | - Paul Mastrokostas
- Department of Chemistry, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America
| | - Evan Kello
- Department of Chemistry, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America
| | - Yosef Gedailovich
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America
| | - Devorah Segall
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America
| | - Alexis Rizzo
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America
| | - Lawrence Mitelberg
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America
| | - Naif Hassan
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America
| | - Terry Lynne Dowd
- Department of Chemistry, Brooklyn College of the City University of New York, Brooklyn, NY 11210, United States of America; Ph.D. Program in Chemistry and Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, United States of America.
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22
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Martiniakova M, Biro R, Kovacova V, Babikova M, Zemanova N, Mondockova V, Omelka R. Current knowledge of bone-derived factor osteocalcin: its role in the management and treatment of diabetes mellitus, osteoporosis, osteopetrosis and inflammatory joint diseases. J Mol Med (Berl) 2024; 102:435-452. [PMID: 38363329 PMCID: PMC10963459 DOI: 10.1007/s00109-024-02418-8] [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: 08/30/2023] [Revised: 12/21/2023] [Accepted: 01/10/2024] [Indexed: 02/17/2024]
Abstract
Osteocalcin (OC) is the most abundant non-collagenous and osteoblast-secreted protein in bone. It consists of two forms such as carboxylated OC (cOC) and undercarboxylated OC (ucOC). While cOC promotes bone mineralization and increases bone strength, ucOC is regarded an endocrinologically active form that may have several functions in multiple end organs and tissues. Total OC (tOC) includes both of these forms (cOC and ucOC) and is considered a marker of bone turnover in clinical settings. Most of the data on OC is limited to preclinical studies and therefore may not accurately reflect the situation in clinical conditions. For the stated reason, the aim of this review was not only to summarize current knowledge of all forms of OC and characterize its role in diabetes mellitus, osteoporosis, osteopetrosis, inflammatory joint diseases, but also to provide new interpretations of its involvement in the management and treatment of aforementioned diseases. In this context, special emphasis was placed on available clinical trials. Significantly lower levels of tOC and ucOC could be associated with the risk of type 2 diabetes mellitus. On the contrary, tOC level does not seem to be a good indicator of high bone turnover status in postmenopausal osteoporosis, osteoarthritis and rheumatoid arthritis. The associations between several pharmacological drugs used to treat all disorders mentioned above and OC levels have also been provided. From this perspective, OC may serve as a medium through which certain medications can influence glucose metabolism, body weight, adiponectin secretion, and synovial inflammation.
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Affiliation(s)
- Monika Martiniakova
- Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Tr. A. Hlinku 1, 949 01, Nitra, Slovakia
| | - Roman Biro
- Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Tr. A. Hlinku 1, 949 01, Nitra, Slovakia
| | - Veronika Kovacova
- Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Tr. A. Hlinku 1, 949 01, Nitra, Slovakia
| | - Martina Babikova
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Tr. A. Hlinku 1, 949 01, Nitra, Slovakia
| | - Nina Zemanova
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Tr. A. Hlinku 1, 949 01, Nitra, Slovakia
| | - Vladimira Mondockova
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Tr. A. Hlinku 1, 949 01, Nitra, Slovakia
| | - Radoslav Omelka
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, Tr. A. Hlinku 1, 949 01, Nitra, Slovakia.
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23
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Jiang W, Caruana DL, Back J, Lee FY. Unique Spatial Transcriptomic Profiling of the Murine Femoral Fracture Callus: A Preliminary Report. Cells 2024; 13:522. [PMID: 38534368 PMCID: PMC10969736 DOI: 10.3390/cells13060522] [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: 02/03/2024] [Revised: 03/07/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
Fracture callus formation is a dynamic stage of bone activity and repair with precise, spatially localized gene expression. Metastatic breast cancer impairs fracture healing by disrupting bone homeostasis and imparting an altered genomic profile. Previous sequencing techniques such as single-cell RNA and in situ hybridization are limited by missing spatial context and low throughput, respectively. We present a preliminary approach using the Visium CytAssist spatial transcriptomics platform to provide the first spatially intact characterization of genetic expression changes within an orthopedic model of impaired fracture healing. Tissue slides prepared from BALB/c mice with or without MDA-MB-231 metastatic breast cancer cells were used. Both unsupervised clustering and histology-based annotations were performed to identify the hard callus, soft callus, and interzone for differential gene expression between the wild-type and pathological fracture model. The spatial transcriptomics platform successfully localized validated genes of the hard (Dmp1, Sost) and soft callus (Acan, Col2a1). The fibrous interzone was identified as a region of extensive genomic heterogeneity. MDA-MB-231 samples demonstrated downregulation of the critical bone matrix and structural regulators that may explain the weakened bone structure of pathological fractures. Spatial transcriptomics may represent a valuable tool in orthopedic research by providing temporal and spatial context.
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Affiliation(s)
| | | | | | - Francis Y. Lee
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, 47 College Place, New Haven, CT 06510, USA
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24
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Correa Pinto Junior D, Canal Delgado I, Yang H, Clemenceau A, Corvelo A, Narzisi G, Musunuri R, Meyer Berger J, Hendricks LE, Tokumura K, Luo N, Li H, Oury F, Ducy P, Yadav VK, Li X, Karsenty G. Osteocalcin of maternal and embryonic origins synergize to establish homeostasis in offspring. EMBO Rep 2024; 25:593-615. [PMID: 38228788 PMCID: PMC10897216 DOI: 10.1038/s44319-023-00031-3] [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: 08/25/2023] [Revised: 11/24/2023] [Accepted: 12/01/2023] [Indexed: 01/18/2024] Open
Abstract
Many physiological osteocalcin-regulated functions are affected in adult offspring of mothers experiencing unhealthy pregnancy. Furthermore, osteocalcin signaling during gestation influences cognition and adrenal steroidogenesis in adult mice. Together these observations suggest that osteocalcin may broadly function during pregnancy to determine organismal homeostasis in adult mammals. To test this hypothesis, we analyzed in unchallenged wildtype and Osteocalcin-deficient, newborn and adult mice of various genotypes and origin maintained on different genetic backgrounds, the functions of osteocalcin in the pancreas, liver and testes and their molecular underpinnings. This analysis revealed that providing mothers are Osteocalcin-deficient, Osteocalcin haploinsufficiency in embryos hampers insulin secretion, liver gluconeogenesis, glucose homeostasis, testes steroidogenesis in adult offspring; inhibits cell proliferation in developing pancreatic islets and testes; and disrupts distinct programs of gene expression in these organs and in the brain. This study indicates that osteocalcin exerts dominant functions in most organs it influences. Furthermore, through their synergistic regulation of multiple physiological functions, osteocalcin of maternal and embryonic origins contributes to the establishment and maintenance of organismal homeostasis in newborn and adult offspring.
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Affiliation(s)
- Danilo Correa Pinto Junior
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Isabella Canal Delgado
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Haiyang Yang
- Guangdong Provincial Key Laboratory of Brain Connectome, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China
| | - Alisson Clemenceau
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | | | | | | | - Julian Meyer Berger
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Lauren E Hendricks
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Kazuya Tokumura
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, Japan
| | - Na Luo
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Hongchao Li
- Guangdong Provincial Key Laboratory of Brain Connectome, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China
| | - Franck Oury
- INSERM U1151, Institut Necker Enfants-Malades (INEM), Université Paris Descartes-Sorbonne, Paris Cité, Paris, France.
| | - Patricia Ducy
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Vijay K Yadav
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Xiang Li
- Guangdong Provincial Key Laboratory of Brain Connectome, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China.
| | - Gerard Karsenty
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
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25
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Zhao Y, Peng X, Wang Q, Zhang Z, Wang L, Xu Y, Yang H, Bai J, Geng D. Crosstalk Between the Neuroendocrine System and Bone Homeostasis. Endocr Rev 2024; 45:95-124. [PMID: 37459436 DOI: 10.1210/endrev/bnad025] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Indexed: 01/05/2024]
Abstract
The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.
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Affiliation(s)
- Yuhu Zhao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Xiaole Peng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Qing Wang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Zhiyu Zhang
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Liangliang Wang
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, China
| | - Yaozeng Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Jiaxiang Bai
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
- Department of Orthopedics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230022, China
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
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26
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Xiang Y, Lu W, Mao X, Zou J, Wang J, Xu R, Tang Q. Osteocalcin has a muscle-protective effect during weight loss in men without metabolic syndrome: a multicenter, prospective, observational study. Front Endocrinol (Lausanne) 2023; 14:1308452. [PMID: 38093960 PMCID: PMC10716436 DOI: 10.3389/fendo.2023.1308452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/17/2023] [Indexed: 12/18/2023] Open
Abstract
Objective Weight reduction often accompanies muscle loss. Existing studies highlight the involvement of osteocalcin (OC) in energy metabolism and its potential to prevent age-related muscle loss. Nevertheless, these studies predominantly involve individuals with hyperglycemia, yielding conflicting research outcomes. This study investigated the protective role of OC against muscle loss during weight reduction in individuals without metabolic syndrome (MetS). Measures We enrolled 130 overweight or obese individuals without MetS in a 4-month high-protein, energy-restricted dietary weight management program conducted at two clinic centers. Body composition and laboratory tests were assessed both before and after weight loss. Correlation and regression analysis were made between the changes in metabolic indicators and muscle mass during weight loss. Results Following weight loss, there was a decrease in body mass index (BMI), percentage of body fat (PBF), visceral fat area (VFA), fasting insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR), glycated haemoglobin (HbA1c), and lipid profile, and increase in the percentage of skeletal muscle (PSM) and vitamin D. There was no change in osteocalcin (OC) during the intervention. Correlation analysis of the relative changes in all metabolic indicators revealed a positive correlation between OC and PSM (r=0.383, p=0.002). Multiple linear regression analysis found that OC has a significant protective effect on muscles during weight loss in males after adjusting for confounding factors (β=0.089, p=0.017). Conclusion High-protein, energy-restricted diets demonstrate efficacy in enhancing metabolic indicators within the weight-loss population. Furthermore, OC exhibits a protective effect on muscle mass during weight reduction in individuals without MetS, with this effect being particularly evident in males.
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Affiliation(s)
- Yi Xiang
- Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenyi Lu
- Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaomeng Mao
- Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Zou
- Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jialu Wang
- Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Renying Xu
- Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qingya Tang
- Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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27
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Wells KV, Krackeler ML, Jathal MK, Parikh M, Ghosh PM, Leach JK, Genetos DC. Prostate cancer and bone: clinical presentation and molecular mechanisms. Endocr Relat Cancer 2023; 30:e220360. [PMID: 37226936 PMCID: PMC10696925 DOI: 10.1530/erc-22-0360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 05/24/2023] [Indexed: 05/26/2023]
Abstract
Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has fewer treatment options and shorter patient survival. PCa and bone health are strongly entwined, as PCa commonly metastasizes to the skeleton. Since androgen receptor signaling drives PCa growth, androgen-deprivation therapy whose sequelae reduce bone strength constitutes the foundation of advanced PCa treatment. The homeostatic process of bone remodeling - produced by concerted actions of bone-building osteoblasts, bone-resorbing osteoclasts, and regulatory osteocytes - may also be subverted by PCa to promote metastatic growth. Mechanisms driving skeletal development and homeostasis, such as regional hypoxia or matrix-embedded growth factors, may be subjugated by bone metastatic PCa. In this way, the biology that sustains bone is integrated into adaptive mechanisms for the growth and survival of PCa in bone. Skeletally metastatic PCa is difficult to investigate due to the entwined nature of bone biology and cancer biology. Herein, we survey PCa from origin, presentation, and clinical treatment to bone composition and structure and molecular mediators of PCa metastasis to bone. Our intent is to quickly yet effectively reduce barriers to team science across multiple disciplines that focuses on PCa and metastatic bone disease. We also introduce concepts of tissue engineering as a novel perspective to model, capture, and study complex cancer-microenvironment interactions.
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Affiliation(s)
- Kristina V Wells
- Department of Anatomy, Physiology, and Cell Biology, University of California Davis School of Veterinary Medicine, Davis, California, USA
| | - Margaret L Krackeler
- Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, California, USA
| | - Maitreyee K Jathal
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA
- Veterans Affairs-Northern California Health System, Mather, California, USA
| | - Mamta Parikh
- Division of Hematology and Oncology, School of Medicine, University of California Davis, Sacramento, California, USA
| | - Paramita M Ghosh
- Veterans Affairs-Northern California Health System, Mather, California, USA
- Department of Urologic Surgery, School of Medicine, University of California Davis, Sacramento, California, USA
| | - J Kent Leach
- Department of Orthopaedic Surgery, School of Medicine, University of California Davis, Sacramento, California, USA
- Department of Biomedical Engineering, University of California Davis, Davis, California, USA
| | - Damian C Genetos
- Department of Anatomy, Physiology, and Cell Biology, University of California Davis School of Veterinary Medicine, Davis, California, USA
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28
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Pinto DC, Delgado IC, Yang H, Clemenceau A, Corvelo A, Narzisi G, Musunuri R, Berger JM, Hendricks LE, Tokumura K, Luo N, Li H, Oury F, Ducy P, Yadav VK, Li X, Karsenty G. Osteocalcin of maternal and embryonic origins synergize to establish homeostasis in offspring. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.11.552969. [PMID: 37645714 PMCID: PMC10462025 DOI: 10.1101/2023.08.11.552969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Many physiological functions regulated by osteocalcin are affected in adult offspring of mothers experiencing an unhealthy pregnancy. Furthermore, osteocalcin signaling during gestation influences cognition and adrenal steroidogenesis in adult mice. Together these observations suggest that osteocalcin functions during pregnancy may be a broader determinant of organismal homeostasis in adult mammals than previously thought. To test this hypothesis, we analyzed in unchallenged wildtype and Osteocalcin -deficient, newborn, and adult mice of various genotypes and origin, and that were maintained on different genetic backgrounds, the functions of osteocalcin in the pancreas, liver and testes and their molecular underpinnings. This analysis revealed that providing mothers are themselves Osteocalcin -deficient, Osteocalcin haploinsufficiency in embryos hampers insulin secretion, liver gluconeogenesis, glucose homeostasis, testes steroidogenesis in adult offspring; inhibits cell proliferation in developing pancreatic islets and testes; and disrupts distinct programs of gene expression in these organs and in the brain. This study indicates that through their synergistic regulation of multiple physiological functions, osteocalcin ofmaternal and embryonic origins contributes to the establishment and maintenance of organismal homeostasis in newborn and adult offspring.
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29
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Khosla S. Evidence in Humans for Bone as an Endocrine Organ Regulating Energy Metabolism. CURRENT OPINION IN ENDOCRINE AND METABOLIC RESEARCH 2023; 31:100471. [PMID: 37576432 PMCID: PMC10417886 DOI: 10.1016/j.coemr.2023.100471] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
There is increasing evidence from animal models that bone, in addition to its traditional function of providing structural support for the organism, has a rich network of interactions with multiple other tissues. This perspective focuses on evidence from human studies demonstrating that bone is an endocrine organ regulating energy metabolism, with the specific examples being osteocalcin, lipocalin 2, RANKL, and sclerostin. Conversely, animal studies have also demonstrated that a key hormone regulating energy metabolism, leptin, regulates bone metabolism via the sympathetic nervous system. Studies in humans have established a role for the sympathetic nervous system in regulating bone turnover; indeed, the potential therapeutic benefit of targeting this pathway in humans to prevent postmenopausal bone loss is currently being evaluated.
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Affiliation(s)
- Sundeep Khosla
- Kogod Center on Aging and Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota
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30
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Yang Y, Tseng WJ, Wang B. Abaloparatide Maintains Normal Rat Blood Calcium Level in Part Via 1,25-Dihydroxyvitamin D/osteocalcin Signaling Pathway. Endocrinology 2023; 164:bqad117. [PMID: 37493045 PMCID: PMC10424883 DOI: 10.1210/endocr/bqad117] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 06/01/2023] [Accepted: 07/25/2023] [Indexed: 07/27/2023]
Abstract
The PTH-related peptide(1-34) analog, abaloparatide (ABL), is the second anabolic drug available for the treatment of osteoporosis. Previous research demonstrated that ABL had a potent anabolic effect but caused hypercalcemia at a significantly lower rate. However, the mechanism by which ABL maintains the stability of blood calcium levels remains poorly understood. Our in vivo data showed that ABL treatment (40 µg/kg/day for 7 days) significantly increased rat blood level of 1,25-dihydroxyvitamin D [1,25-(OH)2D] without raising the blood calcium value. ABL also significantly augmented the carboxylated osteocalcin (Gla-Ocn) in the blood and bone that is synthesized by osteoblasts, and increased noncarboxylated Ocn, which is released from the bone matrix to the circulation because of osteoclast activation. The in vitro data showed that ABL (10 nM for 24 hours) had little direct effects on 1,25-(OH)2D synthesis and Gla-Ocn formation in nonrenal cells (rat osteoblast-like cells). However, ABL significantly promoted both 1,25-(OH)2D and Gla-Ocn formation when 25-hydroxyvitamin D, the substrate of 1α-hydroxylase, was added to the cells. Thus, the increased 1,25-(OH)2D levels in rats treated by ABL result in high levels of Gla-Ocn and transient calcium increase in the circulation. Gla-Ocn then mediates calcium ions in the extracellular fluid at bone sites to bind to hydroxyapatite at bone surfaces. This regulation by Gla-Ocn at least, in part, maintains the stability of blood calcium levels during ABL treatment. We conclude that the signaling pathway of ABL/1,25-(OH)2D/Gla-Ocn contributes to calcium homeostasis and may help understand the mechanism of ABL for osteoporosis therapy.
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Affiliation(s)
- Yanmei Yang
- The Center for Translational Medicine, Departments of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Wei-Ju Tseng
- The Center for Translational Medicine, Departments of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Bin Wang
- The Center for Translational Medicine, Departments of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
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31
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Toyama S, Honda T, Iwabuchi S, Hashimoto S, Yamaji K, Tokunaga Y, Matsumoto Y, Kawaji H, Miyazaki T, Kikkawa Y, Kohara M. Application of spatial transcriptomics analysis using the Visium system for the mouse nasal cavity after intranasal vaccination. Front Immunol 2023; 14:1209945. [PMID: 37545501 PMCID: PMC10403337 DOI: 10.3389/fimmu.2023.1209945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 07/03/2023] [Indexed: 08/08/2023] Open
Abstract
Intranasal vaccines that elicit mucosal immunity are deemed effective against respiratory tract infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but their ability to induce humoral immunity characterized by immunoglobulin A (IgA) and IgG production is low. It has been reported that vaccination with a mixture of a viscous base carboxyvinyl polymer (CVP) and viral antigens induced robust systemic and mucosal immune responses. In this study, we analyzed the behavior of immunocompetent cells in the nasal cavity over time by spatial transcriptome profiling induced immediately after antigen vaccination using CVP. We established a method for performing spatial transcriptomics using the Visium system in the mouse nasal cavity and analyzed gene expression profiles within the nasal cavity after intranasal vaccination. Glycoprotein 2 (Gp2)-, SRY-box transcription factor 8 (Sox8)-, or Spi-B transcription factor (Spib)-expressing cells were increased in the nasal passage (NP) region at 3-6 hr after SARS-CoV-2 spike protein and CVP (S-CVP) vaccination. The results suggested that microfold (M) cells are activated within a short period of time (3-6 hr). Subsequent cluster analysis of cells in the nasal cavity showed an increase in Cluster 9 at 3-6 hr after intranasal vaccination with the S-CVP. We found that Il6 in Cluster 9 had the highest log2 fold values within the NP at 3-6 hr. A search for gene expression patterns similar to that of Il6 revealed that the log2 fold values of Edn2, Ccl20, and Hk2 also increased in the nasal cavity after 3-6 hr. The results showed that the early response of immune cells occurred immediately after intranasal vaccination. In this study, we identified changes in gene expression that contribute to the activation of M cells and immunocompetent cells after intranasal vaccination of mice with antigen-CVP using a time-series analysis of spatial transcriptomics data. The results facilitated the identification of the cell types that are activated during the initial induction of nasal mucosal immunity.
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Affiliation(s)
- Sakiko Toyama
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Tomoko Honda
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Sadahiro Iwabuchi
- Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Shinichi Hashimoto
- Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kenzaburo Yamaji
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Yuko Tokunaga
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Yusuke Matsumoto
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Transboundary Animal Diseases Research Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
| | - Hideya Kawaji
- Research Center for Genome and Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Takashi Miyazaki
- Business Management Department, Toko Yakuhin Kogyo Co., Ltd., Toyama, Japan
| | - Yoshiaki Kikkawa
- Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
- Deafness Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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Shimonty A, Bonewald LF, Huot JR. Metabolic Health and Disease: A Role of Osteokines? Calcif Tissue Int 2023; 113:21-38. [PMID: 37193929 DOI: 10.1007/s00223-023-01093-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/01/2023] [Indexed: 05/18/2023]
Abstract
Maintenance of skeletal health is tightly regulated by osteocytes, osteoblasts, and osteoclasts via coordinated secretion of bone-derived factors, termed osteokines. Disruption of this coordinated process due to aging and metabolic disease promotes loss of bone mass and increased risk of fracture. Indeed, growing evidence demonstrates that metabolic diseases, including type 2 diabetes, liver disease and cancer are accompanied by bone loss and altered osteokine levels. With the persistent prevalence of cancer and the growing epidemic of metabolic disorders, investigations into the role of inter-tissue communication during disease progression are on the rise. While osteokines are imperative for bone homeostasis, work from us and others have identified that osteokines possess endocrine functions, exerting effects on distant tissues including skeletal muscle and liver. In this review we first discuss the prevalence of bone loss and osteokine alterations in patients with type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cirrhosis, and cancer. We then discuss the effects of osteokines in mediating skeletal muscle and liver homeostasis, including RANKL, sclerostin, osteocalcin, FGF23, PGE2, TGF-β, BMPs, IGF-1 and PTHrP. To better understand how inter-tissue communication contributes to disease progression, it is essential that we include the bone secretome and the systemic roles of osteokines.
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Affiliation(s)
- Anika Shimonty
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lynda F Bonewald
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Joshua R Huot
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Kinesiology, School of Health and Human Sciences, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
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33
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Sivagurunathan U, Dominguez D, Tseng Y, Zamorano MJ, Philip AJP, Izquierdo M. Interaction between Dietary Vitamin D 3 and Vitamin K 3 in Gilthead Seabream Larvae ( Sparus aurata) in Relation to Growth and Expression of Bone Development-Related Genes. AQUACULTURE NUTRITION 2023; 2023:3061649. [PMID: 37260465 PMCID: PMC10229253 DOI: 10.1155/2023/3061649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/01/2023] [Accepted: 05/12/2023] [Indexed: 06/02/2023]
Abstract
Vitamins D and K are essential fat-soluble nutrients that intervene in bone development processes among other biological functions. The present study is aimed at investigating the potential combined effect of dietary supplementation with vitamin D3 (cholecalciferol) and vitamin K3 (menadione) in gilthead seabream (Sparus aurata) larvae. For that purpose, seabream diets were supplemented with different combinations of vitamin D3/vitamin K3 (mg/kg diet) as follows: 0.00/0, 0.06/70, 0.06/170, 0.13/70, 0.13/170, 0.40/70, and 0.40/170. Feeding gilthead seabream larvae (22 days post hatch) for 21 days with the diets supplemented with 0.06-0.13 mg/kg vitamin D3 and 70 mg/kg vitamin K3 (diets 0.06/70 and 0.13/70) led to the highest larval growth and survival and the highest expression of important biomarkers of both bone development and health, such as bmp2, osx, and mgp, and calcium homeostasis, such as pthrp and casr. However, the increased supplementation with both vitamins at 0.40 mg/kg vitamin D3 and 170 mg/kg vitamin K3 (diet 0.40/170) reduced larval growth and survival, downregulated bmp2 and pthrp expressions, and upregulated osx and mgp, causing an unbalance in the relative expression of these genes. The results of the present study have shown the interaction between vitamin D3 supplementation and vitamin K3 supplementation in larval performance and gene expression related to bone development and calcium homeostasis, denoting the significance of a correct balance between both vitamins in larval diets.
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Affiliation(s)
- U. Sivagurunathan
- Grupo de Investigación en Acuicultura (GIA), EcoAqua Institute, University of Las Palmas de Gran Canaria, Crta. Taliarte s/n, 35214 Telde, Spain
| | - David Dominguez
- Grupo de Investigación en Acuicultura (GIA), EcoAqua Institute, University of Las Palmas de Gran Canaria, Crta. Taliarte s/n, 35214 Telde, Spain
| | - Yiyen Tseng
- Grupo de Investigación en Acuicultura (GIA), EcoAqua Institute, University of Las Palmas de Gran Canaria, Crta. Taliarte s/n, 35214 Telde, Spain
| | - María Jesús Zamorano
- Grupo de Investigación en Acuicultura (GIA), EcoAqua Institute, University of Las Palmas de Gran Canaria, Crta. Taliarte s/n, 35214 Telde, Spain
| | | | - Marisol Izquierdo
- Grupo de Investigación en Acuicultura (GIA), EcoAqua Institute, University of Las Palmas de Gran Canaria, Crta. Taliarte s/n, 35214 Telde, Spain
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Abstract
Although osteoblasts and osteocytes are descended from the same lineage, they each have unique and essential roles in bone. Targeting gene deletion to osteoblasts and osteocytes using the Cre/loxP system has greatly increased our current understanding of how these cells function. Additionally, the use of the Cre/loxP system in conjunction with cell-specific reporters has enabled lineage tracing of these bone cells both in vivo and ex vivo. However, concerns have been raised regarding the specificity of the promoters used and the resulting off-target effects on cells within and outside of the bone. In this review, we have summarized the main mouse models that have been used to determine the functions of specific genes in osteoblasts and osteocytes. We discuss the expression patterns and specificity of the different promoter fragments during osteoblast to osteocyte differentiation in vivo. We also highlight how their expression in non-skeletal tissues may complicate the interpretation of study results. A thorough understanding of when and where these promoters are activated will enable improved study design and greater confidence in data interpretation.
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Affiliation(s)
- Y Kitase
- Indiana Center for Musculoskeletal Health, Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, United States of America
| | - M Prideaux
- Indiana Center for Musculoskeletal Health, Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, United States of America.
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35
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Tu W, Zhang Y, Jiang K, Jiang S. Osteocalcin and Its Potential Functions for Preventing Fatty Liver Hemorrhagic Syndrome in Poultry. Animals (Basel) 2023; 13:ani13081380. [PMID: 37106943 PMCID: PMC10135196 DOI: 10.3390/ani13081380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/20/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Osteocalcin (OCN) is synthesized and secreted by differentiating osteoblasts. In addition to its role in bone, OCN acts as a hormone in the pancreas, liver, muscle, fat, and other organs to regulate multiple pathophysiological processes including glucose homeostasis and adipic acid metabolism. Fat metabolic disorder, such as excessive fat buildup, is related to non-alcoholic fatty liver disease (NAFLD) in humans. Similarly, fatty liver hemorrhage syndrome (FLHS) is a metabolic disease in laying hens, resulting from lipid accumulation in hepatocytes. FLHS affects hen health with significant impact on poultry egg production. Many studies have proposed that OCN has protective function in mammalian NAFLD, but its function in chicken FLHS and related mechanism have not been completely clarified. Recently, we have revealed that OCN prevents laying hens from FLHS through regulating the JNK pathway, and some pathways related to the disease progression have been identified through both in vivo and vitro investigations. In this view, we discussed the current findings for predicting the strategy for using OCN to prevent or reduce FLHS impact on poultry production.
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Affiliation(s)
- Wenjun Tu
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Yuhan Zhang
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Kunyu Jiang
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Sha Jiang
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China
- Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 402460, China
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36
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Xu Z, Yang C, Wu F, Tan X, Guo Y, Zhang H, Wang H, Sui X, Xu Z, Zhao M, Jiang S, Dai Z, Li Y. Triple-gene deletion for osteocalcin significantly impairs the alignment of hydroxyapatite crystals and collagen in mice. Front Physiol 2023; 14:1136561. [PMID: 37057181 PMCID: PMC10089303 DOI: 10.3389/fphys.2023.1136561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Osteocalcin (Ocn), also known as bone Gla protein, is synthesized by osteoblasts and thought to regulate energy metabolism, testosterone synthesis and brain development. However, its function in bone is not fully understood. Mice have three Ocn genes: Bglap, Bglap2 and Bglap3. Due to the long span of these genes in the mouse genome and the low expression of Bglap3 in bone, researchers commonly use Bglap and Bglap2 knockout mice to investigate the function of Ocn. However, it is unclear whether Bglap3 has any compensatory mechanisms when Bglap and Bglap2 are knocked out. Considering the controversy surrounding the role of Ocn in bone, we constructed an Ocn-deficient mouse model by knocking out all three genes (Ocn−/−) and analyzed bone quality by Raman spectroscopy (RS), Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and MicroCT (μCT). The RS test showed that the alignment of hydroxyapatite crystals and collagen fibers was significantly poorer in Ocn−/− mice than in wild-type (WT) mice. Ocn deficiency resulted in a looser surface structure of bone particles and a larger gap area proportion. FTIR analysis showed few differences in bone mineral index between WT and Ocn−/− mice, while μCT analysis showed no significant difference in cortical and trabecular regions. However, under tail-suspension simulating bone loss condition, the disorder of hydroxyapatite and collagen fiber alignment in Ocn−/− mice led to more obvious changes in bone mineral composition. Collectively, our results revealed that Ocn is necessary for regulating the alignment of minerals parallel to collagen fibrils.
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Affiliation(s)
- Zihan Xu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Chao Yang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
- *Correspondence: Chao Yang, ; Zhongquan Dai, ; Yinghui Li,
| | - Feng Wu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xiaowen Tan
- Department of Pathology and Forensics, Dalian Medical University, Dalian, China
| | - Yaxiu Guo
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Hongyu Zhang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Hailong Wang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xiukun Sui
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Zi Xu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Minbo Zhao
- Department of Pathology and Forensics, Dalian Medical University, Dalian, China
| | - Siyu Jiang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Zhongquan Dai
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
- *Correspondence: Chao Yang, ; Zhongquan Dai, ; Yinghui Li,
| | - Yinghui Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
- *Correspondence: Chao Yang, ; Zhongquan Dai, ; Yinghui Li,
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37
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Inoue K, Qin Y, Xia Y, Han J, Yuan R, Sun J, Xu R, Jiang JX, Greenblatt MB, Zhao B. Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis, and bone mass. eLife 2023; 12:e82118. [PMID: 36779851 PMCID: PMC10005769 DOI: 10.7554/elife.82118] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 02/12/2023] [Indexed: 02/14/2023] Open
Abstract
M-CSF is a critical growth factor for myeloid lineage cells, including monocytes, macrophages, and osteoclasts. Tissue-resident macrophages in most organs rely on local M-CSF. However, it is unclear what specific cells in the bone marrow produce M-CSF to maintain myeloid homeostasis. Here, we found that Adipoq-lineage progenitors but not mature adipocytes in bone marrow or in peripheral adipose tissue, are a major cellular source of M-CSF, with these Adipoq-lineage progenitors producing M-CSF at levels much higher than those produced by osteoblast lineage cells. The Adipoq-lineage progenitors with high CSF1 expression also exist in human bone marrow. Deficiency of M-CSF in bone marrow Adipoq-lineage progenitors drastically reduces the generation of bone marrow macrophages and osteoclasts, leading to severe osteopetrosis in mice. Furthermore, the osteoporosis in ovariectomized mice can be significantly alleviated by the absence of M-CSF in bone marrow Adipoq-lineage progenitors. Our findings identify bone marrow Adipoq-lineage progenitors as a major cellular source of M-CSF in bone marrow and reveal their crucial contribution to bone marrow macrophage development, osteoclastogenesis, bone homeostasis, and pathological bone loss.
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Affiliation(s)
- Kazuki Inoue
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special SurgeryNew YorkUnited States
- Department of Medicine, Weill Cornell Medical CollegeNew YorkUnited States
| | - Yongli Qin
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special SurgeryNew YorkUnited States
- Department of Medicine, Weill Cornell Medical CollegeNew YorkUnited States
| | - Yuhan Xia
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special SurgeryNew YorkUnited States
- Department of Medicine, Weill Cornell Medical CollegeNew YorkUnited States
| | - Jie Han
- The first Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cells, State Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen UniversityXiamenChina
| | - Ruoxi Yuan
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special SurgeryNew YorkUnited States
- Department of Medicine, Weill Cornell Medical CollegeNew YorkUnited States
| | - Jun Sun
- Pathology and Laboratory Medicine, Weill Cornell Medical CollegeNew YorkUnited States
| | - Ren Xu
- The first Affiliated Hospital of Xiamen University-ICMRS Collaborating Center for Skeletal Stem Cells, State Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen UniversityXiamenChina
| | - Jean X Jiang
- Department of Biochemistry & Structural Biology, University of Texas Health Science Center at San AntonioSan AntonioUnited States
| | - Matthew B Greenblatt
- Pathology and Laboratory Medicine, Weill Cornell Medical CollegeNew YorkUnited States
- Research Institute, Hospital for Special SurgeryNew YorkUnited States
| | - Baohong Zhao
- Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special SurgeryNew YorkUnited States
- Department of Medicine, Weill Cornell Medical CollegeNew YorkUnited States
- Graduate Program in Cell and Development Biology, Weill Cornell Graduate School of Medical SciencesNew YorkUnited States
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38
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Cassidy A, Onal M, Pelletier S. Novel methods for the generation of genetically engineered animal models. Bone 2023; 167:116612. [PMID: 36379415 PMCID: PMC9936561 DOI: 10.1016/j.bone.2022.116612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/15/2022]
Abstract
Genetically modified mouse models have shaped our understanding of biological systems in both physiological and pathological conditions. For decades, mouse genome engineering has relied on transgenesis and spontaneous gene replacement in embryonic stem (ES) cells. While these technologies provided a wealth of knowledge, they remain imprecise and expensive to use. Recent advances in genome editing technologies such as the development of targetable nucleases, the improvement of delivery systems, and the simplification of targeting strategies now allow for the rapid, precise manipulation of the mouse genome. In this review article, we discuss novel methods and targeting strategies for the generation of mouse models for the study of bone and skeletal muscle biology.
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Affiliation(s)
- Annelise Cassidy
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Melda Onal
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Stephane Pelletier
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
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39
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Alonso N, Meinitzer A, Fritz-Petrin E, Enko D, Herrmann M. Role of Vitamin K in Bone and Muscle Metabolism. Calcif Tissue Int 2023; 112:178-196. [PMID: 35150288 PMCID: PMC9859868 DOI: 10.1007/s00223-022-00955-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/26/2022] [Indexed: 01/25/2023]
Abstract
Vitamin K, a cofactor for the γ-glutamyl carboxylase enzyme, is required for the post-translational activation of osteocalcin and matrix Gla protein, which play a key role in bone and muscle homeostasis. In vivo and in vitro models for osteoporosis and sarcopenia suggest the vitamin K could exert a positive effect in both conditions. In bone, it increases osteoblastogenesis, whilst decreases osteoclast formation and function. In muscle, it is associated with increased satellite cell proliferation and migration and might play a role in energy metabolism. Observational trials suggest that high levels of vitamin K are associated with increased bone mineral density and reduced fracture risk. However, interventional studies for vitamin K supplementation yielded conflicting results. Clinical trials in sarcopenia suggest that vitamin K supplementation could improve muscle mass and function. One of the main limitations on the vitamin K studies are the technical challenges to measure its levels in serum. Thus, they are obtained from indirect sources like food questionnaires, or levels of undercarboxylated proteins, which can be affected by other environmental or biological processes. Although current research appoints to a beneficial effect of vitamin K in bone and muscle, further studies overcoming the current limitations are required in order to incorporate this supplementation in the clinical management of patients with osteosarcopenia.
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Affiliation(s)
- N Alonso
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - A Meinitzer
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - E Fritz-Petrin
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - D Enko
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - M Herrmann
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
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40
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Wong L, McMahon LP. Crosstalk between bone and muscle in chronic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1146868. [PMID: 37033253 PMCID: PMC10076741 DOI: 10.3389/fendo.2023.1146868] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/14/2023] [Indexed: 04/11/2023] Open
Abstract
With increasing life expectancy, the related disorders of bone loss, metabolic dysregulation and sarcopenia have become major health threats to the elderly. Each of these conditions is prevalent in patients with chronic kidney disease (CKD), particularly in more advanced stages. Our current understanding of the bone-muscle interaction is beyond mechanical coupling, where bone and muscle have been identified as interrelated secretory organs, and regulation of both bone and muscle metabolism occurs through osteokines and myokines via autocrine, paracrine and endocrine systems. This review appraises the current knowledge regarding biochemical crosstalk between bone and muscle, and considers recent progress related to the role of osteokines and myokines in CKD, including modulatory effects of physical exercise and potential therapeutic targets to improve musculoskeletal health in CKD patients.
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Affiliation(s)
- Limy Wong
- Department of Renal Medicine, Monash University Eastern Health Clinical School, Box Hill, VIC, Australia
- Department of Renal Medicine, Eastern Health, Box Hill, VIC, Australia
- *Correspondence: Limy Wong,
| | - Lawrence P. McMahon
- Department of Renal Medicine, Monash University Eastern Health Clinical School, Box Hill, VIC, Australia
- Department of Renal Medicine, Eastern Health, Box Hill, VIC, Australia
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41
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Schini M, Vilaca T, Gossiel F, Salam S, Eastell R. Bone Turnover Markers: Basic Biology to Clinical Applications. Endocr Rev 2022; 44:417-473. [PMID: 36510335 PMCID: PMC10166271 DOI: 10.1210/endrev/bnac031] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 11/26/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022]
Abstract
Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide; and commonly used resorption markers serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen and tartrate resistant acid phosphatase type 5b. BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable components (e.g., age, gender, ethnicity) and controllable components, particularly relating to collection conditions (e.g., fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics; and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget's disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.
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Affiliation(s)
- Marian Schini
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.,Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Tatiane Vilaca
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Fatma Gossiel
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Syazrah Salam
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.,Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Richard Eastell
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
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Abstract
The mammalian skeleton is integral to whole body physiology with a multitude of functions beyond mechanical support and locomotion, including support of hematopoiesis, mineral homeostasis and potentially other endocrine roles. Formation of the skeleton begins in the embryo and mostly from a cartilage template that is ultimately replaced by bone through endochondrial ossification. Skeletal development and maturation continue after birth in most species and last into the second decade of postnatal life in humans. In the mature skeleton, articular cartilage lining the synovial joint surfaces is vital for bodily movement and damages to the cartilage are a hallmark of osteoarthritis. The mature bone tissue undergoes continuous remodeling initiated with bone resorption by osteoclasts and completed with bone formation from osteoblasts. In a healthy state, the exquisite balance between bone resorption and formation is responsible for maintaining a stable bone mass and structural integrity, while meeting the physiological needs for minerals via controlled release from bone. Disruption of the balance in favor of bone resorption is the root cause for osteoporosis. Whereas osteoclasts pump molar quantities of hydrochloric acid to dissolve the bone minerals in a process requiring ATP hydrolysis, osteoblasts build bone mass by synthesizing and secreting copious amounts of bone matrix proteins. Thus, both osteoclasts and osteoblasts engage in energy-intensive activities to fulfill their physiological functions, but the bioenergetics of those and other skeletal cell types are not well understood. Nonetheless, the past ten years have witnessed a resurgence of interest in studies of skeletal cell metabolism, resulting in an unprecedented understanding of energy substrate utilization and its role in cell fate and activity regulation. The present review attempts to synthesize the current findings of glucose metabolism in chondrocytes, osteoblasts and osteoclasts. Advances with the other relevant cell types including skeletal stem cells and marrow adipocytes will not be discussed here as they have been extensively reviewed recently by others (van Gastel and Carmeliet, 2021). Elucidation of the bioenergetic mechanisms in the skeletal cells is likely to open new avenues for developing additional safe and effective bone therapies.
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Affiliation(s)
- Fanxin Long
- Translational Research Program in Pediatric Orthopedics, The Children's Hospital of Philadelphia, Department of Orthopedic Surgery, University of Pennsylvania, United States of America
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Weber DR, Long F, Zemel BS, Kindler JM. Glycemic Control and Bone in Diabetes. Curr Osteoporos Rep 2022; 20:379-388. [PMID: 36214991 PMCID: PMC9549036 DOI: 10.1007/s11914-022-00747-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/30/2022] [Indexed: 01/30/2023]
Abstract
PURPOSE OF REVIEW This review summarizes recent developments on the effects of glycemic control and diabetes on bone health. We discuss the foundational cellular mechanisms through which diabetes and impaired glucose control impact bone biology, and how these processes contribute to bone fragility in diabetes. RECENT FINDINGS Glucose is important for osteoblast differentiation and energy consumption of mature osteoblasts. The role of insulin is less clear, but insulin receptor deletion in mouse osteoblasts reduces bone formation. Epidemiologically, type 1 (T1D) and type 2 diabetes (T2D) associate with increased fracture risk, which is greater among people with T1D. Accumulation of cortical bone micro-pores, micro-vascular complications, and AGEs likely contribute to diabetes-related bone fragility. The effects of youth-onset T2D on peak bone mass attainment and subsequent skeletal fragility are of particular concern. Further research is needed to understand the effects of hyperglycemia on skeletal health through the lifecycle, including the related factors of inflammation and microvascular damage.
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Affiliation(s)
- David R Weber
- Division of Endocrinology and Diabetes, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia,, PA, USA
| | - Fanxin Long
- Department of Orthopedic Surgery, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Babette S Zemel
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- Division of GI, Hepatology & Nutrition, Roberts Center for Pediatric Research, 2716 South Street, 14th Floor/Room 14471, Philadelphia, PA, 19146, USA.
| | - Joseph M Kindler
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA
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Clarke P, Shearer MJ, Card DJ, Nichols A, Ponnusamy V, Mahaveer A, Voong K, Dockery K, Holland N, Mulla S, Hall LJ, Maassen C, Lux P, Schurgers LJ, Harrington DJ. Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth. J Thromb Haemost 2022; 20:2773-2785. [PMID: 36087073 PMCID: PMC9828794 DOI: 10.1111/jth.15874] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 07/25/2022] [Accepted: 08/25/2022] [Indexed: 01/13/2023]
Abstract
BACKGROUND There is near-global consensus that all newborns be given parenteral vitamin K1 (VK1 ) at birth as prophylaxis against VK deficiency bleeding (VKDB). Breastmilk has a low VK content and cases of late VKDB are reported in exclusively breastmilk-fed preterm infants despite VK prophylaxis at birth. OBJECTIVES To assess the prevalence of functional VK insufficiency in preterm infants based on elevated under-γ-carboxylated (Glu) species of Gla proteins, factor II (PIVKA-II), and osteocalcin (GluOC), synthesized by liver and bone, respectively. PATIENTS/METHODS Prospective, multicenter, observational study in preterm infants born <33 weeks' gestation. Blood samples and dietary history were collected before hospital discharge, and after discharge at 2-3 months' corrected age. Outcome measures were serum VK1 , PIVKA-II, and %GluOC (GluOC as a percentage of the sum of GluOC plus GlaOC) compared between exclusively breastmilk-fed and formula/mixed-fed infants after discharge. RESULTS After discharge, breastmilk-fed babies had significantly lower serum VK1 (0.15 vs. 1.81 μg/L), higher PIVKA-II (0.10 vs. 0.02 AU/ml) and higher %GluOC (63.6% vs. 8.1%) than those receiving a formula/mixed-feed diet. Pre-discharge (based on elevated PIVKA-II), only one (2%) of 45 breastmilk-fed infants was VK insufficient. After discharge, eight (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only one (4%) of 25 formula/mixed-fed babies. CONCLUSIONS Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK1 supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.
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Affiliation(s)
- Paul Clarke
- Neonatal Intensive Care UnitNorfolk and Norwich University Hospitals NHS Foundation TrustNorwichUK
- Norwich Medical SchoolUniversity of East AngliaNorwichUK
| | - Martin J. Shearer
- Centre for Haemostasis and ThrombosisGuy's and St Thomas's NHS Foundation TrustLondonUK
| | - David J. Card
- Nutristasis Unit, Viapath, Guy's and St Thomas's NHS Foundation TrustLondonUK
| | - Amy Nichols
- Neonatal Intensive Care UnitNorfolk and Norwich University Hospitals NHS Foundation TrustNorwichUK
| | - Vennila Ponnusamy
- Neonatal Intensive Care UnitAshford and St Peter's Hospitals NHS Foundation TrustChertseyUK
| | - Ajit Mahaveer
- Neonatal Intensive Care Unit, St Mary's HospitalManchester University NHS Foundation TrustManchesterUK
| | - Kieran Voong
- Centre for Haemostasis and ThrombosisGuy's and St Thomas's NHS Foundation TrustLondonUK
| | - Karen Dockery
- Neonatal Intensive Care Unit, St Mary's HospitalManchester University NHS Foundation TrustManchesterUK
| | - Nicky Holland
- Neonatal Intensive Care UnitAshford and St Peter's Hospitals NHS Foundation TrustChertseyUK
| | - Shaveta Mulla
- Neonatal Intensive Care UnitNorfolk and Norwich University Hospitals NHS Foundation TrustNorwichUK
| | - Lindsay J. Hall
- Gut Microbes & HealthQuadram Institute BioscienceNorwichUK
- ZIEL – Institute for Food & HealthTechnical University of MunichFreisingGermany
| | - Cecile Maassen
- Department of BiochemistryCardiovascular Research Institute MaastrichtMaastricht UniversityMaastrichtThe Netherlands
| | - Petra Lux
- Department of BiochemistryCardiovascular Research Institute MaastrichtMaastricht UniversityMaastrichtThe Netherlands
| | - Leon J. Schurgers
- Department of BiochemistryCardiovascular Research Institute MaastrichtMaastricht UniversityMaastrichtThe Netherlands
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Wang YJ, Jin CH, Ke JF, Wang JW, Ma YL, Lu JX, Li MF, Li LX. Decreased Serum Osteocalcin is an Independent Risk Factor for Metabolic Dysfunction-Associated Fatty Liver Disease in Type 2 Diabetes. Diabetes Metab Syndr Obes 2022; 15:3717-3728. [PMID: 36471670 PMCID: PMC9719286 DOI: 10.2147/dmso.s389794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/15/2022] [Indexed: 11/30/2022] Open
Abstract
PURPOSE The association between serum osteocalcin (OCN) levels and metabolic dysfunction-associated fatty liver disease (MAFLD) is still controversial. Moreover, few studies have explored their relationship in type 2 diabetes mellitus (T2DM) patients so far. The present study aimed to investigate the association of serum OCN levels with MAFLD in Chinese T2DM patients. METHODS This cross-sectional, real-world study included 1889 Chinese T2DM inpatients. MAFLD was diagnosed by abdominal ultrasonography. Participants were divided into four groups according to serum OCN quartiles, among which the clinical characteristics were compared. The association of serum OCN levels with the presence of MAFLD was also analyzed in subjects. RESULTS After controlling for sex, age, and diabetes duration, the prevalence of MAFLD significantly decreased across the serum OCN quartiles (55.3%, 52.0%, 48.6%, and 42.1% for the first, second, third, and fourth quartiles, respectively, P < 0.001 for trend). A fully adjusted multiple logistic regression analysis showed that serum OCN levels were independently and negatively associated with the presence of MAFLD in T2DM patients (odds ratio, 0.832; 95% confidence interval, 0.719-0.962; P = 0.013). Furthermore, there were significant decreases in HOMA-IR (P = 0.001 for trend) and C-reactive protein (P < 0.001 for trend) levels across the serum OCN quartiles after controlling for sex, age, and diabetes duration. CONCLUSION Serum OCN levels were independently and negatively associated with the presence of MAFLD in Chinese T2DM patients, partially due to the improvement of insulin resistance and inflammation mediated by OCN. Serum OCN may be used as a biomarker to assess the risk of MAFLD in T2DM patients.
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Affiliation(s)
- Yu-Jie Wang
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of China
| | - Chun-Hua Jin
- Department of Endocrinology and Metabolism, Shanghai Songjiang District Central Hospital, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Preparatory Stage), Shanghai, People’s Republic of China
| | - Jiang-Feng Ke
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of China
| | - Jun-Wei Wang
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of China
| | - Yi-Lin Ma
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of China
| | - Jun-Xi Lu
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of China
| | - Mei-Fang Li
- Department of Emergency, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Lian-Xi Li
- Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, People’s Republic of China
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Matthaei M, Kononov S, Rehage J, Szura G, Leiter I, Hansen K, Daenicke S, von Soosten D, Kersten S, Meyer U, Wilkens M. Does bone mobilization interfere with energy metabolism in transition cows? JDS COMMUNICATIONS 2022; 3:451-455. [PMID: 36465511 PMCID: PMC9709610 DOI: 10.3168/jdsc.2022-0239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/26/2022] [Indexed: 06/01/2023]
Abstract
The onset of lactation represents a challenge for both mineral homeostasis and energy metabolism in high-performing dairy cows. It has been shown that subclinical and clinical hypocalcemia increases the risk of ketosis and recent studies suggest that bone-derived endocrine factors could play a role in intermediary metabolism. Therefore, we analyzed serum samples from calculated d -7, calculated d -3, d +1, d +3, and d +7 relative to calving from 15 multiparous cows for total Ca, the bone resorption marker CrossLaps, the bone formation marker intact osteocalcin, undercarboxylated osteocalcin (ucOC), insulin, glucose, nonesterified fatty acids, β-hydroxybutyrate, and insulin-like growth factor 1. Serum concentrations of Ca on d -3 and d +1 were associated with parameters of energy metabolism on d +3 and d +7. As we found large variations for serum concentrations of ucOC already on d -7, we allocated the cows retrospectively to 3 groups: low ucOC, medium ucOC, and high ucOC. These groups differed not only in their ucOC dynamics, but also in insulin sensitivity estimated using the revised quantitative insulin sensitivity index (RQUICKI). High ucOC cows presented with the highest RQUICKI throughout the entire observation period. Our data further support the hypothesis that low serum Ca precedes disturbances of energy metabolism. Furthermore, from our preliminary results it can be assumed that the potential link between mineral homeostasis, bone turnover, and intermediary metabolism should be further investigated.
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Affiliation(s)
- M.O. Matthaei
- Institute of Animal Nutrition, Nutrition Diseases and Dietetics, Faculty of Veterinary Medicine, University of Leipzig, 01403 Leipzig, Saxony, Germany
| | - S.U. Kononov
- Institute of Animal Nutrition, Nutrition Diseases and Dietetics, Faculty of Veterinary Medicine, University of Leipzig, 01403 Leipzig, Saxony, Germany
| | - J. Rehage
- Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Lower Saxony, Germany
| | - G. Szura
- Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Lower Saxony, Germany
| | - I. Leiter
- Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Lower Saxony, Germany
| | - K. Hansen
- Institute of Physiology and Cell Biology, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Lower Saxony, Germany
| | - S. Daenicke
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, 38116 Braunschweig, Lower Saxony, Germany
| | - D. von Soosten
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, 38116 Braunschweig, Lower Saxony, Germany
| | - S. Kersten
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, 38116 Braunschweig, Lower Saxony, Germany
| | - Ulrich Meyer
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, 38116 Braunschweig, Lower Saxony, Germany
| | - M.R. Wilkens
- Institute of Animal Nutrition, Nutrition Diseases and Dietetics, Faculty of Veterinary Medicine, University of Leipzig, 01403 Leipzig, Saxony, Germany
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Zhao F, Yang Z, Xiong H, Yan Y, Chen X, Shao L. A bioactive glass functional hydrogel enhances bone augmentation via synergistic angiogenesis, self-swelling and osteogenesis. Bioact Mater 2022; 22:201-210. [PMID: 36246665 PMCID: PMC9535384 DOI: 10.1016/j.bioactmat.2022.09.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/28/2022] [Accepted: 09/12/2022] [Indexed: 12/03/2022] Open
Abstract
Bone augmentation materials usually cannot provide enough new bone for dental implants due to the material degradation and mucosal pressure. The use of hydrogels with self-swelling properties may provide a higher bone augmentation, although swelling is generally considered to be a disadvantage in tissue engineering. Herein, a double-crosslinked gelatin-hyaluronic acid hydrogels (GH) with self-swelling properties were utilized. Meanwhile, niobium doped bioactive glasses (NbBG) was dispersed in the hydrogel network to prepare the GH-NbBG hydrogel. The composite hydrogel exhibited excellent biocompatibility and the addition of NbBG significantly improved the mechanical properties of the hydrogel. In vivo results found that GH-NbBG synergistically promoted angiogenesis and increased bone augmentation by self-swelling at the early stage of implantation. In addition, at the late stage after implantation, GH-NbBG significantly promoted new bone formation by activating RUNX2/Bglap signaling pathway. Therefore, this study reverses the self-swelling disadvantage of hydrogels into advantage and provides novel ideas for the application of hydrogels in bone augmentation.
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Affiliation(s)
- Fujian Zhao
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Zhen Yang
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, China,National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
| | - Huacui Xiong
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Yang Yan
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, China,National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
| | - Xiaofeng Chen
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, China,National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China,Corresponding author. Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510641, China.
| | - Longquan Shao
- Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China,Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Guangzhou, 510515, China,Corresponding author. Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China.
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Jawich K, Rocca MS, Al Fahoum S, Alhalabi M, Di Nisio A, Foresta C, Ferlin A, De Toni L. RS 2247911 polymorphism of GPRC6A gene and serum undercarboxylated-osteocalcin are associated with testis function. J Endocrinol Invest 2022; 45:1673-1682. [PMID: 35482214 DOI: 10.1007/s40618-022-01803-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 04/07/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Undercarboxylated-Osteocalcin (ucOCN), acting on its putative receptor GPRC6A, was shown to stimulate testosterone (T) production by Leydig cells in rodents, in parallel with the hypothalamus-pituitary-gonadal axis (HPG) mediated by luteinizing hormone (LH). The aim of this cross-sectional study was to evaluate the association among serum ucOCN, rs2247911 polymorphism of GPRC6A gene and the endocrine/semen pattern in a cohort of infertile males, possibly identifying an involvement of the ucOCN-GPRC6A axis on testis function. METHODS 190 males, including 74 oligozoospermic subjects, 58 azoosperminc patients and 58 normozoospermic controls, were prospectively recruited at the Orient Hospital for Infertility, Assisted Reproduction and Genetics in Syria (Study N. 18FP), from July 2018 to June 2020. Outpatient evaluation included the clinical history, anthropometrics and a fasting blood sampling for hormonals, serum OCN (both carboxylated and undercarboxylated), glycemic and lipid profile and screening for rs2247911 GPRC6A gene polymorphism. RESULTS Higher serum ucOCN associated with higher T and HDL-cholesterol (respectively: r = 0.309, P < 0.001 and r = 0.248, P = 0.001), and with lower FSH (r = - 0.327, P < 0.001) and LDL-cholesterol (r = - 0.171; P = 0.018). Patients bearing the GG genotype of rs2247911 had higher sperm count compared to GA genotype (P = 0.043) and, compared to both AG and AA genotypes, had higher serum T (P = 0.004, P = 0.001) and lower triglycerides levels (P = 0.002, P < 0.001). Upon normalization for LH levels and body mass index, rs2274911 and ucOCN were significantly associated with higher serum T at linear stepwise regression analysis (P = 0.013, P = 0.007). CONCLUSIONS Our data suggest the involvement of ucOCN-GPRC6A axis in the regulation of T production by the testis, subsidiary to HPG.
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Affiliation(s)
- K Jawich
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syrian Arab Republic
| | - M Santa Rocca
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padua, Italy
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, Padua, Italy
| | - S Al Fahoum
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syrian Arab Republic.
| | - M Alhalabi
- Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic
| | - A Di Nisio
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padua, Italy
| | - C Foresta
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padua, Italy
| | - A Ferlin
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padua, Italy
| | - L De Toni
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padua, Italy
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Liu S, Shen G, Li W. Structural and cellular basis of vitamin K antagonism. J Thromb Haemost 2022; 20:1971-1983. [PMID: 35748323 DOI: 10.1111/jth.15800] [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: 05/02/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 11/30/2022]
Abstract
Vitamin K antagonists (VKAs), such as warfarin, are oral anticoagulants widely used to treat and prevent thromboembolic diseases. Therapeutic use of these drugs requires frequent monitoring and dose adjustments, whereas overdose often causes severe bleeding. Addressing these drawbacks requires mechanistic understandings at cellular and structural levels. As the target of VKAs, vitamin K epoxide reductase (VKOR) generates the active, hydroquinone form of vitamin K, which in turn drives the γ-carboxylation of several coagulation factors required for their activity. Crystal structures revealed that VKAs inhibit VKOR via mimicking its catalytic process. At the active site, two strong hydrogen bonds that facilitate the catalysis also afford the binding specificity for VKAs. Binding of VKAs induces a global change from open to closed conformation. Similar conformational change is induced by substrate binding to promote an electron transfer process that reduces the VKOR active site. In the cellular environment, reducing partner proteins or small reducing molecules may afford electrons to maintain the VKOR activity. The catalysis and VKA inhibition require VKOR in different cellular redox states, explaining the complex kinetics behavior of VKAs. Recent studies also revealed the mechanisms underlying warfarin resistance, warfarin dose variation, and antidoting by vitamin K. These mechanistic understandings may lead to improved anticoagulation strategies targeting the vitamin K cycle.
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Affiliation(s)
- Shixuan Liu
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Guomin Shen
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA
- Henan International Joint Laboratory of Thrombosis and Hemostasis, School of Basic Medical Science, Henan University of Science and Technology, Luoyang, China
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Weikai Li
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA
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50
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Yuan W, Song C. Crosstalk between bone and other organs. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:331-348. [PMID: 37724328 PMCID: PMC10471111 DOI: 10.1515/mr-2022-0018] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/06/2022] [Indexed: 09/20/2023]
Abstract
Bone has long been considered as a silent organ that provides a reservoir of calcium and phosphorus, traditionally. Recently, further study of bone has revealed additional functions as an endocrine organ connecting systemic organs of the whole body. Communication between bone and other organs participates in most physiological and pathological events and is responsible for the maintenance of homeostasis. Here, we present an overview of the crosstalk between bone and other organs. Furthermore, we describe the factors mediating the crosstalk and review the mechanisms in the development of potential associated diseases. These connections shed new light on the pathogenesis of systemic diseases and provide novel potential targets for the treatment of systemic diseases.
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Affiliation(s)
- Wanqiong Yuan
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China
| | - Chunli Song
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China
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