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Investigating the role of Tfam-mediated mitochondrial respiration in osteoblastogenesis

Award Number: F32AR088407
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Investigating the role of Tfam-mediated mitochondrial respiration in osteoblastogenesis - PROJECT SUMMARY Bone fragility and osteoporotic fractures are major complications of aging and metabolic diseases. Osteoblast differentiation, which drives osteogenesis, bone mass accrual, and bone repair, is an energetically demanding process easily disrupted by impaired glucose metabolism. While glucose has repeatedly been shown to be the primary fuel for osteoblasts, it remains controversial whether these cells generate ATP through glycolysis or through mitochondrial oxidative phosphorylation (OxPhos) across osteoblastogenesis. Studies of early osteoprogenitors in the mesenchymal limb bud have suggested that OxPhos-derived ATP is required for proper bone formation and growth; by contrast, we and others have demonstrated that mature osteoblasts are largely glycolytic ex vivo, and that OxPhos is dispensable for overall ATP production in these cells. These models imply a developmental shift in energy metabolism from OxPhos to glycolysis, but direct in vivo evidence defining the timing, necessity, and functional significance of this transition is lacking. To resolve these conflicting reports, we generated mice in which the mitochondrial transcription factor, Tfam, is conditionally deleted only in the committed osteoblast lineage (Sp7/Osterix-expressing cells) onward. Tfam is a nuclear protein required for expression of the electron transport chain in mitochondria, and thus, OxPhos, as well as for mitochondrial DNA replication. This approach bypasses the effects of Tfam deletion in early progenitors and isolates mitochondrial requirements to committed osteoblasts. Preliminary data indicate that, unlike in earlier deletion models such as Prx1-cre, Tfam loss in Sp7-expressing cells does not affect bone mass or architecture. Based on these results and our prior studies, I therefore hypothesize that Tfam-dependent mitochondrial OxPhos is dispensable for bioenergetics and function in preosteoblasts and mature osteoblasts. To test this hypothesis, I will 1) comprehensively characterize the effects of Sp7-mediated Tfam-cKO on bone formation and osteoblastogenesis and 2) determine the bioenergetic consequences of Tfam-deletion on osteoblast function, and isolate potential non-bioenergetic roles for osteoblast mitochondria during osteogenesis. Together, these studies will delineate the role of osteoblast mitochondria in skeletal formation. By clarifying when and why mitochondrial respiration is required or dispensable, this work will provide a novel framework for understanding the energy demands of osteogenesis and identify potentially novel intervention strategies for osteoporotic bone loss and fracture associated with metabolic disease. Accomplishing the aims proposed herein will provide training in experimental methods to study localized and systemic metabolism and strengthen both my benchwork and analytical skills. Above all, this fellowship will provide a solid foundation from which to launch my future career as a principal investigator and found my own laboratory focused on the role of intercellular bioenergetic resource distribution in homeostasis and metabolic disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $76,300 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/1/2026	NEW	$0
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/1/2026	NEW	$76,300
														Subtotal = $76,300

Grand Total All Awards = $76,300

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Investigating the role of Tfam-mediated mitochondrial respiration in osteoblastogenesis

Award Number: F32AR088407

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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