Clinical studies report that children born with severe hyperhomocysteinemia (HHcy), due to deficiency in cystathionine-?-synthase (CBS) gene, resulting in an elevation in plasma homocysteine (Hcy) levels, develop skeletal malformations with weaker bone. Although mitochondrial dysfunction has been involved in bone pathology, altered mitochondrial (Mito) epigenetics and dynamics contributing to frailer bone have not been studied. The long term goal of this project is to understand the mechanisms of mito-epigenetic remodeling and changes in bone structure/function during genetic HHcy. Alterations in mitochondrial dynamics disturb bone cell (osteoclast/ osteoblast) differentiation and matrix metabolism. Studies have confirmed that type-I collagen (coll-1), a dominant protein of the organic bone matrix, is homocysteinylated (N-Hcy-coll-1) during HHcy. Our preliminary data suggest that genetic HHcy affects mito-epigenetic remodeling by altering mito-redox stress, mito-DNA methylation / hydroxymethylation, fission-fusion and cause N-Hcy-coll-1 cross linking. These processes cumulatively disrupt bone matrix, bone density, bone blood flow and lead to mitophagy accompanying with significant bone loss. Interestingly, hydrogen sulfide (H2S, an anti-redox stress and Hcy lowering agent) mitigates bone damage. The central hypothesis of this proposal is that HHcy contributes to bone-matrix inferiority through N-Hcy-coll-1, in part, by increasing mito- epigenetic remodeling and altering mitochondrial dynamics. However, treatment with H2S ameliorates HHcy-induced bone abnormalities. We will test this hypothesis by following three specific Aims:
Specific Aim # 1: To determine whether the HHcy instigates mito-epigenetic remodeling and DNA methylation, in part, by altering mitochondrial fission and fusion, and whether H2S mitigates mito-epigenetic remodeling.
Specific Aim # 2: To determine whether the HHcy homocysteinylates bone type-I collagen, activates MMP-1,-3,-13, disrupts bone matrix (MMP/TIMP axis; collagen/elastin ratio) and H2S ameliorates these changes.
Specific Aim # 3: To determine whether the HHcy alters bone mineral density, bone mineral content, biomechanical load-bearing capacity, bone blood flow and disrupts osteoblast/osteoclast differentiation and whether H2S alleviates these alterations.

Public Health Relevance

The proposed project will delineate the novel molecular, pathological and functional mechanisms for bone deformity by incorporating mitochondrial epigenetics and dynamics studies during hyperhomocysteinemia. The involvement of knockout (MMP9- /-), gene deficient (CBS+/-), double knockout (CBS+/-/MMP9-/-) mice and their various treatments (for example; 5'-azacytidine, Mdivi-1, pyridoxal 5' phosphate) will come up with exciting results and innovative findings that have never been studied in bone pathology. Also, the use of hydrogen sulfide throughout the study will not only validate the pathways but also confirm its therapeutic aspects in bone diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Chen, Faye H
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University of Louisville
Schools of Medicine
United States
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Behera, Jyotirmaya; Kelly, Kimberly E; Voor, Michael J et al. (2018) Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism. Sci Rep 8:15226
Behera, Jyotirmaya; George, Akash K; Voor, Michael J et al. (2018) Hydrogen sulfide epigenetically mitigates bone loss through OPG/RANKL regulation during hyperhomocysteinemia in mice. Bone 114:90-108
George, Akash K; Behera, Jyotirmaya; Kelly, Kimberly E et al. (2018) Exercise Mitigates Alcohol Induced Endoplasmic Reticulum Stress Mediated Cognitive Impairment through ATF6-Herp Signaling. Sci Rep 8:5158
Behera, Jyotirmaya; Tyagi, Neetu (2018) Exosomes: mediators of bone diseases, protection, and therapeutics potential. Oncoscience 5:181-195
Vacek, Jonathan C; Behera, Jyotirmaya; George, Akash K et al. (2018) Tetrahydrocurcumin ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells. J Cell Physiol 233:3080-3092
Behera, Jyotirmaya; Bala, Jyoti; Nuru, Mohammed et al. (2017) Homocysteine as a Pathological Biomarker for Bone Disease. J Cell Physiol 232:2704-2709
Zhai, Yuankun; Tyagi, Suresh C; Tyagi, Neetu (2017) Cross-talk of MicroRNA and hydrogen sulfide: A novel therapeutic approach for bone diseases. Biomed Pharmacother 92:1073-1084
Theilen, Nicholas T; Kunkel, George H; Tyagi, Suresh C (2017) The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy. J Cell Physiol 232:2348-2358
Veeranki, Sudhakar; Tyagi, Suresh C (2017) Dysbiosis and Disease: Many Unknown Ends, Is It Time to Formulate Guidelines for Dysbiosis Research? J Cell Physiol 232:2929-2930
George, Akash K; Behera, Jyotirmaya; Kelly, Kimberly E et al. (2017) Hydrogen sulfide, endoplasmic reticulum stress and alcohol mediated neurotoxicity. Brain Res Bull 130:251-256

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