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

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Brief Title

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

Official Title

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

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.
    

Detailed Description

      Intact mitochondrial activity including adequate energy supplies is vital for metabolic
      active tissues i.e. skeletal muscle, heart and brain. The human skeleton represent an
      additional highly metabolically active tissue; nevertheless the significance of the
      mitochondrial role in human skeletal bone health may be further investigated.

      Bone remodelling constitutes the coupled and continuous regenerative process of bone
      degradation by bone resorbing cells osteoclasts (OC) followed by formation of bone matrix by
      bone forming osteoblasts (OB). Quantitative imbalance between resorption and formation
      results in skeletal disorders with low bone mass including osteoporosis, and its increased
      risk of fragility fractures.

      Mitochondria generate cellular energy adenosine triphosphate (ATP) through oxidative
      phosphorylation process (OXPHOS) in the respiratory chain (RC) with a secondary production of
      the deleterious by-products free radicals i.e. reactive oxygen species (ROS). Notably,
      mitochondria hold their own DNA (m.DNA), and RC subunits are encoded by m.DNA and nuclear DNA
      (n.DNA) genes, respectively. With ageing, deleterious somatic m.DNA mutations accumulate in
      skeletal muscle and heart, and somatic m.DNA mutations as well as inherited m.DNA or n.DNA
      mutations may result in mitochondrial dysfunction with impaired ATP production and
      accumulation of ROS. m.DNA mutations may impair brain, skeletal-, and cardiac muscle
      function, but the effects on human bone cell metabolism and remodelling are unknown. A recent
      study of a cohort of young individuals indicates that mitochondrial diseases pose a risk for
      bone fragility fractures.

      Preclinical studies suggest that ATP and ROS regulate bone metabolism. The m.DNA number and
      mitochondrial activity increase to support differentiation from human skeletal (mesenchymal)
      stem cells (hMSC) to mature bone forming OBs. Inhibition of mitochondrial activity or
      increase in ROS levels suppress OB differentiation. Similarly, OCs are rich in mitochondria.
      Human OC cultures demonstrate that energy supplies for OC differentiation from their
      progenitors is based on OXPHOS while OC resorption activity relies on glycolysis.

      In addition, emerging evidence suggest that metabolic plasticity i.e. regulation of
      glycolysis, OXPHOS, and pyruvate levels, contribute to regulation of OB and OC
      differentiation.

      Receptor activator of nuclear factor kappa-Beta ligand (RANKL) secreted by OBs activates OC
      resorption. In mice, RANKL stimulation of bone marrow OC progenitors increases intracellular
      levels of ROS, which stimulates OC differentiation and bone resorption in-vitro. Further, ROS
      inhibits the wingless-type (Wnt) signalling pathway with attenuation of osteoblastogenesis
      and decreased bone formation.

      Furthermore, mice with mutations in the n.DNA encoded proof reading domain of m.DNA
      polymerase POLG (PolgA-/-) accumulate m.DNA mutations, and present with premature ageing
      phenotype including low bone mass. In addition, deficiency of the n.DNA encoded mitochondrial
      transcription factor (TFAM) causes ATP depletion, and mice with TFAM deficient OCs have
      increased OC activity and augmented bone resorption. Opposite, global loss of NADH
      (nicotinamide-adenine dinucleotide) ubiquinone oxidoreductase Fe-S protein 4 (NDUFS4) a
      subunit in RC complex 1 impairs bone resorption, and (ndufs4-/-) mice present with increased
      bone mineral density (BMD) and an apparent osteopetrosis bone phenotype.

      The aim is to study bone cell phenotype in patients with rare mitochondrial disease Carriers
      of MT-TL1 m.3243A>G (MIM: 590050).The gene encodes the transcription factor tRNALeu(UUA/UUG)
      and m.3243A>G weakens the assembly of RC complex with a secondary impaired ATP production.
      The phenotype is, in part associated with the m.3243A>G mutation burden i.e. level of
      heteroplasmy (percentage of m.3243A>G/wildtype m.DNA). The study group also includes carriers
      of mutations in the nuclear encoded POLG (MIM: 174763) and TWNK (MIM: 606075).

      Hypothesis: Impaired mitochondrial function affects human bone cell -differentiation,
      -metabolism, and -activity leading to impaired bone formation and bone fragility.

      Aim: To determine if carriers of inherited mitochondrial mutations i.e. mitochondrial
      dysfunction, ATP depletion and secondary increase in ROS lead to change in:

        1. In-vitro OB differentiation-rate, OB activity and bone formation.

        2. In-vitro OC differentiation-, OC activity and higher overall bone resorption.

        3. In-vivo changes in tissues level dynamics of bone formation and - resorption as examined
           in iliac crest bone biopsies.

      Design, Participants and Methods: Cross-sectional case-control study including subjects (>18
      years) carrying one of the following mutations:

        1. MT-TL1 m.3243A>G

        2. POLG mutation

        3. TWNK

      N=10 cases with each pathogenic genetic variant and equal number of controls (n=30) matched
      on sex, age and BMI.
    


Study Type

Interventional


Primary Outcome

Extracellular acidification rate (ECAR) (mpH/min)

Secondary Outcome

 Bone growth rate (µm/day)

Condition

Mitochondrial Diseases

Intervention

Clinical assessment, blood samples, bone marrow and bone biopsy

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

30

Start Date

February 1, 2020

Completion Date

January 1, 2024

Primary Completion Date

August 1, 2023

Eligibility Criteria

        Inclusion Criteria - cases:

        Genetic diagnosis with: MT-TL1 m.3243A>G, or POLG variant,het or TWNK variant, het

        Signed informed consent

        Inclusion Criteria - controls:

        Healthy subjects matched on age and gender

        Signed informed consent

        Exclusion Criteria:

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Anja L Frederiksen, MD, +4597664999, [email protected]

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT05483738

Organization ID

S-20180170


Responsible Party

Principal Investigator

Study Sponsor

Aalborg University Hospital

Collaborators

 Odense University Hospital

Study Sponsor

Anja L Frederiksen, MD, Principal Investigator, Aalborg University Hospital


Verification Date

July 2022