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The Role of MEK5 in Melatonin-induced Osteoblast and Osteoclast Differentiation

Award Number: R15AR068603
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): Our long-term goal is to develop novel therapies to improve bone formation and increase bone density in women and men with osteopenia or osteoporosis. Melatonin is a novel alternative to current treatments because it possesses multiple bone-protective actions by working through a stimulation of osteoblasts, an inhibition of osteoclasts and possibly through its free-radical scavenging properties to protect bone cells against excessive bone resorption. It is expected that long-term use of melatonin in people will prevent osteopenia and osteoporosis and reduce bone fractures through its effects on both osteoblasts and osteoclasts. The objective is to clarify the mechanism(s) underlying melatonin's effects on osteoblasts and osteoclasts in rodent bone and in vitro using a novel co-culture system consisting of human mesenchymal stem cells (hMSCs) and human peripheral blood monocytes (hPBMCs). The project goal is to identify the role of MEK5 and MEK1/2 on regulating melatonin-mediated osteoblastogenesis and osteoclastogenesis using models that more closely mimics what occurs in vivo. Our central hypothesis is that melatonin, through MEK1/2 and 5, will stimulate osteoblastogenesis and inhibit osteoclastogenesis by modulating osteoblast-specific markers, RUNX2, osteocalcin and FRA-1 and by regulating the ratios of osteoprotegerin and RANKL to inhibit osteoclastogenesis, respectively. We plan to objectively test our hypothesis by pursuing the following two specific aims: (1) Assess the effects of MEK5 on melatonin-mediated osteoblast and osteoclast differentiation and signaling in hMSC-hPBMC co-cultures; (2) Assess the role of melatonin and MEK1/2 and 5 on melatonin-mediated changes in osteoblast and osteoclast function, bone formation and density in vivo. These studies will not only clarify the mechanisms underlying melatonin's actions on osteoblasts, osteoclasts and bone but will also identify a novel target (MEK5) for the development of future bone-forming therapies to reduce fracture risk in susceptible populations.


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: 2021 ( Subtotal = -$119 )
2021	2016	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	12/7/2020	NEW	-$119
														Subtotal = -$119

Issue Date FY: 2016 ( Subtotal = $363,999 )
2016	2016	DUQUESNE UNIVERSITY OF THE HOLY GHOST	ADMINISTRATION BLDG, ROOM 211	PITTSBURGH	PA	15282	ALLEGHENY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/1/2016	NEW	$363,999
														Subtotal = $363,999

Grand Total All Awards = $363,880

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The Role of MEK5 in Melatonin-induced Osteoblast and Osteoclast Differentiation

Award Number: R15AR068603

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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