Peak bone and skeletal muscle mass in mammals is highly correlated, suggesting the existence of common anabolic signaling networks in these anatomically adjacent tissues that promote their development. It has been widely assumed, that larger muscles stimulate increased skeletal acquisition indirectly, through force- generated mechanical signals, which transduce anabolic activity in the adjacent bone. Alternatively, these same signaling networks that control muscle mass might function directly in bone. While this latter concept is intuitively appealing, few basic studies have attempted to describe such a pathway. The studies in this application take direct aim at this problem and propose that the activin/myostatin signaling pathway constitutes a common mechanism that regulates the acquisition and maintenance of skeletal mass in a manner analogous to the well-defined activity of this pathway in muscle. In muscle, activation of activin receptor signaling by myostatin and related ligands negatively regulates muscle growth such that blocking signaling via genetic alterations or pharmacologic treatments profoundly increases in muscle mass. Consistent with this idea, we have found that functional components of the activin/myostatin receptors are abundantly expressed in osteoblasts. Further, we demonstrated that short-term treatment (4 IP injections) of a soluble ACVR2B receptor in wild-type mice rapidly (4 weeks) tripled trabecular bone mass, suggesting for the first time that activin signaling directly influences bone acquisition. Based upon these observations, we hypothesize that a subset of activin/myostatin molecules function through specific receptors in osteoblasts to directly inhibit bone acquisition, and that inhibition of such receptor signaling increases bone mass. In this project, we will test this hypothesis by characterizing the activin signaling components in bone and distinguishing them from those that operate in skeletal muscle. We will exploit new mouse models that lack selectively either ACVR2 or ACVR2B in bone to unambiguously identify skeletal actions of activin/myostatin signaling. In a second series of complementary studies, we will further test the significance of the activin pathway on bone and muscle mass, in wild type mice and models of age-related sarcopenia and osteopenia, by administration of soluble activin receptors. We expect the results from the studies proposed in this application will expedite clinical trials of activin receptor-based biologics to treat age-related bone and muscle loss in humans.

Public Health Relevance

This project will use novel genetic mouse models to unambiguously define the direct actions of activin receptor signaling in skeletal development and maintenance. Further, we will evaluate the therapeutic efficacy of pharmacologically manipulating this pathway in a mouse model of age related bone and muscle loss. We anticipate that results from these studies will expedite clinical trials of activin receptor-based biologics to treat bone and muscle loss in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR062074-01
Application #
8220374
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2011-09-21
Project End
2016-07-31
Budget Start
2011-09-21
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$382,752
Indirect Cost
Name
Johns Hopkins University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Goh, Brian C; Singhal, Vandana; Herrera, Angelica J et al. (2017) Activin receptor type 2A (ACVR2A) functions directly in osteoblasts as a negative regulator of bone mass. J Biol Chem 292:13809-13822
DiGirolamo, Douglas J; Singhal, Vandana; Chang, Xiaoli et al. (2015) Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta. Bone Res 3:14042
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DiGirolamo, Douglas J; Kiel, Douglas P; Esser, Karyn A (2013) Bone and skeletal muscle: neighbors with close ties. J Bone Miner Res 28:1509-18
DiGirolamo, Douglas J; Clemens, Thomas L; Kousteni, Stavroula (2012) The skeleton as an endocrine organ. Nat Rev Rheumatol 8:674-83