Our long-term goal is to understand the role and regulation of mitochondrial metabolism in bone physiology and pathology. Unlike other fields, such as cardiovascular and muscle physiology and neuroscience, to date very little effort has been directed towards mitochondrial research in the bone field. This presents an immense knowledge gap and a critical barrier to developing novel mitochondria-targeted strategies for bone pathologies, such as aging and trauma which are known to be associated with mitochondrial dysfunction. This also gives special significance to our mitochondria-centered proposal. Our objective here is to determine the mechanism controlling mitochondrial activity during osteoblastic (OB) differentiation of bone marrow stromal cells (BMSC, a.k.a. bone marrow mesenchymal stem cells) and test if strategies aimed at improving mitochondrial metabo- lism stimulate OB differentiation and bone formation. Our published and new unpublished data indicate that during OB differentiation, mitochondria fuse into a network, a phenomenon known to maximize the fidelity for oxidative phosphorylation (OxPhos). A dangerous byproduct of active OxPhos is oxidative stress which pro- motes opening of a large Mitochondrial Permeability Transition Pore (MPTP). MPTP opening impairs mito- chondrial integrity and function. Cyclophilin D (CypD) is a key positive regulator of MPTP. It is, thus beneficial for cells undergoing a shift towards oxidative metabolism, e.g. BMSCs differentiating into OBs, to inactivate CypD/MPTP. We indeed found that as mitochondria become fused and activated during OB differentiation, CypD is downregulated at the mRNA level ensuring protection against oxidative stress and supporting OxPhos and progression of OB program. Moreover, our data indicate that CypD genetic deletion in knockout (KO) mice or pharmacological inhibition is especially efficient in supporting OB oxidative and bone forming function under pathological stress, such as in aging and fracture. We recently reported that CypD KO mice are well protected against bone loss in aging. This is consistent with the literature showing that brain, heart, and kidney tissues of CypD KO mice are protected against degeneration in aging or ischemic injury. All this led us to hypothesize that mitochondrial fusion and CypD downregulation leading to activation of OxPhos and inhibition of MPTP dur- ing OB differentiation, are critical for OB differentiation. To test this hypothesis and fulfill our objective, we will: 1) characterize the mechanism by which mitochondria are activated during OB differentiation focusing on mito- chondrial fusion; 2) characterize the role and regulation of CypD/MPTP during OB differentiation; and 3) evalu- ate CypD as a therapeutic target to improve bone formation in fracture healing and aging. These studies will provide comprehensive understanding of regulation of mitochondrial metabolism during OB differentiation and a rationale for developing new mitochondria-targeted therapeutic strategies in bone.

Public Health Relevance

The proposed research is relevant to public health because it has a potential to lead to development of new strategies to improve bone fracture healing and control bone loss in aging by protecting mitochondria during osteoblastic differentiation of bone marrow stromal/stem cells. It is also expected to advance the field of bone biology by elucidating the yet unknown mechanisms connecting mitochondrial metabolism and bone formation. This is also highly relevant to the NIH mission of developing fundamental knowledge that will help to reduce the burdens of human disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR072601-02
Application #
9644984
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Nicks, Kristy
Project Start
2018-03-01
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Rochester
Department
Orthopedics
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627