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The Myokine Irisin Modulates Bone Resorption via Stimulation of Osteoclastogenesis

Award Number: F32AR077382
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: 05/05/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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The Myokine Irisin Modulates Bone Resorption via Stimulation of Osteoclastogenesis - ABSTRACT The myokine irisin is a peptide that is proteolyzed from the muscle-bound protein Fndc5 (fibronectin type III domain-containing protein 5) during exercise and enters circulation and induces a thermogenic program in beige adipose tissue1,2. Several studies have suggested a key role for irisin in mediating the effect of exercise on bone, demonstrating that intermittent low dose irisin (0.1 mg/kg once per week) stimulates cortical bone formation and prevents unloading-induced bone loss in vivo, and enhances osteogenesis in vitro3-5. Utilizing the power of mouse genetics, our group has endeavored to further elucidate the role of irisin in skeletal remodeling, demonstrating that forced expression of Fndc5 in muscle markedly reduces bone formation and mass, decreases osteoblast number while increasing osteoclasts, and increasing NF-κB and SOST expression while suppressing serum levels of bone formation markers. Similarly, genetic deletion of Fndc5 led to high vertebral bone volume and complete protection from ovariectomy (OVX)-induced bone loss in female mice, marked by maintenance of osteocyte lacunae density and size, blocked bone resorption, and no increase in RANKL expression despite prolonged estrogen deprivation. Short term irisin infusions in wild type mice resulted in higher serum levels of sclerostin and greater SOST mRNA expression. Irisin treatment of MLOY-4 osteocytes in vitro demonstrated a direct effect on this cell type, inducing gene and protein level expression of sclerostin in a dose dependent manner and preventing hydrogen peroxide-induced apoptosis. Importantly, we identified through biochemical and biophysical means that the αVβ5 integrin is the principal, although possibly not the only, receptor for irisin in osteocytes6. We now have evidence that in addition to its effect on the osteocyte, irisin acts directly on the osteoclast to stimulate differentiation, and this effect is reversed by blocking both αVβ5 and αVβ3 with antibody antagonists. At face value these data would seem to run counter to the prevailing hypothesis that myokines are purely anabolic for bone. However, in a physiologic context irisin might also indirectly stimulate osteoblasts via release of clastokines or matrix-bound growth factors, or it may have a unique role as a counter regulatory hormone to maintain calcium homeostasis by increasing resorption. With the work proposed herein, we will address two specific aims to test the central hypothesis that irisin acts as a key regulating factor in the influence of exercise on bone remodeling; both by direct action on the osteoclast through integrin αVβ5, and by modulation of osteoclast paracrine signaling with osteocytes and osteoblasts. Because this myokine may play a key role in linking physical activity and bone remodeling, this work will focus both on traditional static in vitro culture models as well as address the effect of mechanical loading such as fluid shear on the osteoclast, osteoblast, and osteocyte with specific regard to the influence of irisin on cell mechanosensitivity.


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: 2024 ( Subtotal = -$4,682 )
2024	2022	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/28/2023	NON-COMPETING CONTINUATION	-$4,682
														Subtotal = -$4,682

Issue Date FY: 2023 ( Subtotal = -$14,740 )
2023	2022	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/31/2023	NON-COMPETING CONTINUATION	-$14,740
														Subtotal = -$14,740

Issue Date FY: 2022 ( Subtotal = $70,582 )
2022	2022	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/3/2022	NON-COMPETING CONTINUATION	$69,802
2022	2021	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/1/2022	NON-COMPETING CONTINUATION	$780
														Subtotal = $70,582

Issue Date FY: 2021 ( Subtotal = $66,510 )
2021	2021	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/10/2021	NON-COMPETING CONTINUATION	$66,510
														Subtotal = $66,510

Issue Date FY: 2020 ( Subtotal = $67,626 )
2020	2020	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/5/2020	NEW	$67,626
														Subtotal = $67,626

Grand Total All Awards = $185,296

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The Myokine Irisin Modulates Bone Resorption via Stimulation of Osteoclastogenesis

Award Number: F32AR077382

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: 05/05/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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