Wednesday, January 21, 2026 1/21/2026

Rescuing impaired fracture healing by molecular targeting

Award Number: R01AR081656
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

Group Awards By:

View Award Description

Rescuing impaired fracture healing by molecular targeting - Project Summary:This A1 proposal focuses on impaired pathological fracture healing in the presence of breast cancer cells, not on the entire complex sequence of cancer spread from the breast to bone. Metastatic cancer cells can settle in anywhere in the bone including bone marrow, cortical bone, or outside of the bone. Cancer cells are spilled in and out of bone at the time of fracture. Pathological fracture calluses are deficient and very often fail to ossify despite adjuvant therapies such radiation therapy and anti-resorptive agents including Rank:Fc antibody (denosumab) or bisphosphonates (zoledronate). Failed fracture healing is not solely a result of bone resorption. There is no mechanistic understanding as to why fractures do not heal well in the presence of certain types of breast cancer cells. Unraveling the mechanisms underlying impaired fracture healing will enable patients to benefit from future scientific endeavors employing mechanism-based treatments. If there is a way of addressing impaired fracture repair while also inhibiting cancer growth in bone, the clinical care for pathological fractures will be immensely impacted. We conducted whole transcriptome bulk RNAsequencing of several different types of breast cancer cells that are grown in breast vs. bone. We observed that breast cancer cells that inhibit fracture repair are pro-inflammatory with heightened MEK1-pERK1/2-cytokine- hyperinflammation signaling in the bone microenvironment. Temporal expression of pro-Inflammatory cytokines and bone-acting proteins such as TNF, interleukins, and sclerostin are completely deranged and prolonged following femur fractures in the presence of breast cancer cells such as MDA231, HC1806, and 4T1 However, there is a critical knowledge gap as to how these different breast cancer cell types affect chondro-progenitors, osteoblasts, osteoclasts, and osteocytes within the intact fracture callus architecture as suggested by the Reviewer. Two notable changes in this A1 proposal include the refinement of the animal models and a new set of compelling spatial transcriptomic biology data incorporating the Reviewers’ critiques and suggestions. We posit a central hypothesis that highly inflammatory pERK1/2-high breast cancer cells inhibit the normal fracture callus formation and maturation by causing prolonged hyper-inflammation and subsequent derangements of callus spatial transcriptomics. We propose 3 Specific Aims. Aim 1. To define temporal and spatial transcriptomic changes of inflammatory, osteogenic, and chondrogenic lineage cells in structurally intact fracture callus in vivo. Aim 2. To rescue impaired osteogenesis of osteoprogenitors, chondroprogenitors, and periosteal cells in the presence breast cancer cells by inhibition of pERK1/2-induced inflammation ex vivo. Aim 3. In Vivo Pre-clinical Therapeutic Translation: To establish a mechanism-based rescue of impaired pathological fracture healing by targeting specific pro-inflammatory kinases in vivo. We expect to establish a novel therapeutic paradigm for devastating patients suffering from cancer and pathological fractures.


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 = $449,016 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/9/2026	NON-COMPETING CONTINUATION	$449,016
														Subtotal = $449,016

Issue Date FY: 2025 ( Subtotal = $485,368 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/6/2025	NON-COMPETING CONTINUATION	$35,026
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/20/2024	NON-COMPETING CONTINUATION	$450,342
														Subtotal = $485,368

Issue Date FY: 2024 ( Subtotal = $507,749 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/15/2024	NEW	$507,749
														Subtotal = $507,749

Grand Total All Awards = $1,442,133

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Rescuing impaired fracture healing by molecular targeting

Award Number: R01AR081656

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer