The Impact of Mitochondrial Dysfunction on Human Bone Cell Metabolism and Remodelling

NCT05483738 | Active Not Recruiting

• 1 other identifier: S-20180170
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Cell and mice studies suggest mitochondrial dysfunction may cause altered bone structure. Hypothesis: Decreased mitochondrial energy production affects bone cell development and activity negatively. Comparing humans with the mitochondrial DNA variant, m.3243A\>G, pathogenic variants in POLG or TWNK genes to healthy controls, the aim is to evaluate the effect of mitochondrial dysfunction on: 1: bone-cell development and -activity in bone marrow stem cells and blood. 2: bone cell metabolism including glucose consumption. 3: bone structure assessed by electron microscopy and μCT scans of bone biopsies.

Conditions

Mitochondrial Diseases; Bone Remodeling Disorder

Keywords

m3243A>G; POLG; TWNK; Mitochondria

Outcome Measures

Primary Outcomes (3)

• Extracellular acidification rate (ECAR) (mpH/min)

  Measurement of ECAR in human bone marrow skeletal (mesenchymal) stem cells (hBM-MSCs), osteoblasts (OB) and osteoclasts (OC)

  Up to 12 weeks

• Oxygen consumption rate (OCR) (mpMol/min)

  Measurement of OCR in hBM-MSCs, OBs and OCs

  Up to 12 weeks

• Growth rate (number of cells)

  Growth rate of of OBs and OCs

  Up to 12 weeks

Secondary Outcomes (2)

• Bone growth rate (µm/day)

  Up to 4 weeks

• Histomorphometric

  Up to 4 weeks

Study Arms (1)

Cases and controls

OTHER

Clinical assessment, blood samples, dual energy x-ray absorptiometry (DXA) scan, and assessment of bone marrow, and tetracycline labelled bone biopsy

Diagnostic Test: Clinical assessment, blood samples, bone marrow and bone biopsy

Interventions

Clinical assessment, blood samples, bone marrow and bone biopsy DIAGNOSTIC_TEST

Assessment of blood samples, bone marrow and bone biopsy

Cases and controls

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Genetic diagnosis with: MT-TL1 m.3243A\>G, or POLG variant, het or TWNK variant, het, \> 18 years
• Signed informed consent
• Healthy subjects matched on age and gender \> 18 years
• Signed informed consent

You may not qualify if:

• Renal (creatinine \> 90 µmol/l)
• Liver dysfunction (AST \> 3 times the upper limit)
• Medical treatment influencing bone metabolism (oral corticosteroid \<12 weeks, anti-osteoporosis treatment, sex steroids, anti-convulsants)
• Pregnancy
• Excessive consumption of alcohol
• Treatment with anticoagulants
• Pre-existing coagulopathy
• Allergy to lidocaine, morphine or diazepam.

Sponsors & Collaborators

• Aalborg University Hospital: lead
• Odense University Hospital: collaborator
• University of Southern Denmark: collaborator

Study Sites (1)

Dept. of Clinical Genetics

Aalborg, Denmark

Location

Related Publications (31)

• Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, Suomalainen A, Thorburn DR, Zeviani M, Turnbull DM. Mitochondrial diseases. Nat Rev Dis Primers. 2016 Oct 20;2:16080. doi: 10.1038/nrdp.2016.80.

  PMID: 27775730 BACKGROUND

• Seeman E, Delmas PD. Bone quality--the material and structural basis of bone strength and fragility. N Engl J Med. 2006 May 25;354(21):2250-61. doi: 10.1056/NEJMra053077. No abstract available.

  PMID: 16723616 BACKGROUND

• Bartell SM, Kim HN, Ambrogini E, Han L, Iyer S, Serra Ucer S, Rabinovitch P, Jilka RL, Weinstein RS, Zhao H, O'Brien CA, Manolagas SC, Almeida M. FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nat Commun. 2014 Apr 30;5:3773. doi: 10.1038/ncomms4773.

  PMID: 24781012 BACKGROUND

• Andreasen CM, Ding M, Overgaard S, Bollen P, Andersen TL. A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep. Bone. 2015 Jun;75:32-9. doi: 10.1016/j.bone.2015.02.014. Epub 2015 Feb 14.

  PMID: 25689083 BACKGROUND

• Kim SJ, Mehta HH, Wan J, Kuehnemann C, Chen J, Hu JF, Hoffman AR, Cohen P. Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY). 2018 Jun 10;10(6):1239-1256. doi: 10.18632/aging.101463.

  PMID: 29886458 BACKGROUND

• Sinha K, Das J, Pal PB, Sil PC. Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 2013 Jul;87(7):1157-80. doi: 10.1007/s00204-013-1034-4. Epub 2013 Mar 30.

  PMID: 23543009 BACKGROUND

• Meissner C, Bruse P, Mohamed SA, Schulz A, Warnk H, Storm T, Oehmichen M. The 4977 bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: a useful biomarker or more? Exp Gerontol. 2008 Jul;43(7):645-652. doi: 10.1016/j.exger.2008.03.004. Epub 2008 Mar 20.

  PMID: 18439778 BACKGROUND

• Lee HC, Wei YH. Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging. Exp Biol Med (Maywood). 2007 May;232(5):592-606.

  PMID: 17463155 BACKGROUND

• Hayashi G, Cortopassi G. Oxidative stress in inherited mitochondrial diseases. Free Radic Biol Med. 2015 Nov;88(Pt A):10-7. doi: 10.1016/j.freeradbiomed.2015.05.039. Epub 2015 Jun 12.

  PMID: 26073122 BACKGROUND

• Gandhi SS, Muraresku C, McCormick EM, Falk MJ, McCormack SE. Risk factors for poor bone health in primary mitochondrial disease. J Inherit Metab Dis. 2017 Sep;40(5):673-683. doi: 10.1007/s10545-017-0046-2. Epub 2017 Apr 27.

  PMID: 28451918 BACKGROUND

• Chen CT, Shih YR, Kuo TK, Lee OK, Wei YH. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells. 2008 Apr;26(4):960-8. doi: 10.1634/stemcells.2007-0509. Epub 2008 Jan 24.

  PMID: 18218821 BACKGROUND

• Gao J, Feng Z, Wang X, Zeng M, Liu J, Han S, Xu J, Chen L, Cao K, Long J, Li Z, Shen W, Liu J. SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress. Cell Death Differ. 2018 Feb;25(2):229-240. doi: 10.1038/cdd.2017.144. Epub 2017 Sep 15.

  PMID: 28914882 BACKGROUND

• Brown D, Breton S. Mitochondria-rich, proton-secreting epithelial cells. J Exp Biol. 1996 Nov;199(Pt 11):2345-58. doi: 10.1242/jeb.199.11.2345.

  PMID: 9114500 BACKGROUND

• Lemma S, Sboarina M, Porporato PE, Zini N, Sonveaux P, Di Pompo G, Baldini N, Avnet S. Energy metabolism in osteoclast formation and activity. Int J Biochem Cell Biol. 2016 Oct;79:168-180. doi: 10.1016/j.biocel.2016.08.034. Epub 2016 Aug 30.

  PMID: 27590854 BACKGROUND

• Arnett TR, Orriss IR. Metabolic properties of the osteoclast. Bone. 2018 Oct;115:25-30. doi: 10.1016/j.bone.2017.12.021. Epub 2017 Dec 21.

  PMID: 29274806 BACKGROUND

• Lee NK, Choi YG, Baik JY, Han SY, Jeong DW, Bae YS, Kim N, Lee SY. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood. 2005 Aug 1;106(3):852-9. doi: 10.1182/blood-2004-09-3662. Epub 2005 Apr 7.

  PMID: 15817678 BACKGROUND

• Garrett IR, Boyce BF, Oreffo RO, Bonewald L, Poser J, Mundy GR. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest. 1990 Mar;85(3):632-9. doi: 10.1172/JCI114485.

  PMID: 2312718 BACKGROUND

• Almeida M, Han L, Martin-Millan M, O'Brien CA, Manolagas SC. Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J Biol Chem. 2007 Sep 14;282(37):27298-27305. doi: 10.1074/jbc.M702811200. Epub 2007 Jul 10.

  PMID: 17623658 BACKGROUND

• Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004 May 27;429(6990):417-23. doi: 10.1038/nature02517.

  PMID: 15164064 BACKGROUND

• Miyazaki T, Iwasawa M, Nakashima T, Mori S, Shigemoto K, Nakamura H, Katagiri H, Takayanagi H, Tanaka S. Intracellular and extracellular ATP coordinately regulate the inverse correlation between osteoclast survival and bone resorption. J Biol Chem. 2012 Nov 2;287(45):37808-23. doi: 10.1074/jbc.M112.385369. Epub 2012 Sep 17.

  PMID: 22988253 BACKGROUND

• Jin Z, Wei W, Yang M, Du Y, Wan Y. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell Metab. 2014 Sep 2;20(3):483-98. doi: 10.1016/j.cmet.2014.07.011. Epub 2014 Aug 14.

  PMID: 25130399 BACKGROUND

• Varanasi SS, Francis RM, Berger CE, Papiha SS, Datta HK. Mitochondrial DNA deletion associated oxidative stress and severe male osteoporosis. Osteoporos Int. 1999;10(2):143-9. doi: 10.1007/s001980050209.

  PMID: 10501795 BACKGROUND

• Kato H, Han X, Yamaza H, Masuda K, Hirofuji Y, Sato H, Pham TTM, Taguchi T, Nonaka K. Direct effects of mitochondrial dysfunction on poor bone health in Leigh syndrome. Biochem Biophys Res Commun. 2017 Nov 4;493(1):207-212. doi: 10.1016/j.bbrc.2017.09.045. Epub 2017 Sep 9.

  PMID: 28899781 BACKGROUND

• Langdahl JH, Frederiksen AL, Hansen SJ, Andersen PH, Yderstraede KB, Duno M, Vissing J, Frost M. Mitochondrial Point Mutation m.3243A>G Associates With Lower Bone Mineral Density, Thinner Cortices, and Reduced Bone Strength: A Case-Control Study. J Bone Miner Res. 2017 Oct;32(10):2041-2048. doi: 10.1002/jbmr.3193. Epub 2017 Jul 18.

  PMID: 28603900 BACKGROUND

• van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, van de Kamp JJ, Maassen JA. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992 Aug;1(5):368-71. doi: 10.1038/ng0892-368.

  PMID: 1284550 BACKGROUND

• Sasarman F, Antonicka H, Shoubridge EA. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet. 2008 Dec 1;17(23):3697-707. doi: 10.1093/hmg/ddn265. Epub 2008 Aug 27.

  PMID: 18753147 BACKGROUND

• Frederiksen AL, Andersen PH, Kyvik KO, Jeppesen TD, Vissing J, Schwartz M. Tissue specific distribution of the 3243A->G mtDNA mutation. J Med Genet. 2006 Aug;43(8):671-7. doi: 10.1136/jmg.2005.039339. Epub 2006 Feb 20.

  PMID: 16490799 BACKGROUND

• Langdahl JH, Larsen M, Frost M, Andersen PH, Yderstraede KB, Vissing J, Duno M, Thomassen M, Frederiksen AL. Lecocytes mutation load declines with age in carriers of the m.3243A>G mutation: A 10-year Prospective Cohort. Clin Genet. 2018 Apr;93(4):925-928. doi: 10.1111/cge.13201.

  PMID: 29266179 BACKGROUND

• Jafari A, Qanie D, Andersen TL, Zhang Y, Chen L, Postert B, Parsons S, Ditzel N, Khosla S, Johansen HT, Kjaersgaard-Andersen P, Delaisse JM, Abdallah BM, Hesselson D, Solberg R, Kassem M. Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis. Stem Cell Reports. 2017 Feb 14;8(2):373-386. doi: 10.1016/j.stemcr.2017.01.003. Epub 2017 Feb 2.

  PMID: 28162997 BACKGROUND

• Abdallah BM, Ditzel N, Kassem M. Assessment of bone formation capacity using in vivo transplantation assays: procedure and tissue analysis. Methods Mol Biol. 2008;455:89-100. doi: 10.1007/978-1-59745-104-8_6.

  PMID: 18463812 BACKGROUND

• Soe K, Delaisse JM. Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle. J Bone Miner Res. 2010 Oct;25(10):2184-92. doi: 10.1002/jbmr.113.

  PMID: 20499345 BACKGROUND

MeSH Terms

Conditions

Mitochondrial Diseases

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Anja L Frederiksen, MD

  Aalborg University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Masking Details: Participants are masked with anonymized identifier (ID)
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, Ph.D, Clinical Professor

Model Details: Matched case-control study

Study Record Dates

• First Submitted: July 22, 2022
• First Posted: August 2, 2022
• Study Start: February 1, 2020
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: October 2, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)