Diseases of low bone mass, particularly osteoporosis, have gravely impacted society, causing massive disability. Current therapies for the restoration of bone mass are limited and focus primarily on the attenuation of osteoclast activity. The development of anabolic therapies that stimulate osteoblast activity and bone mass acquisition is essential; however, our understanding of the underlying mechanisms regulating osteogenic differentiation and bone formation is still incomplete. The work proposed in this grant aims to expand on our knowledge of the molecular mechanisms involved in bone mass acquisition by assessing the role of protein kinase C delta (PKC?) in bone. Although PKC?-/- mice exhibit reduced embryonic bone formation and a cell autonomous defect in osteoblast differentiation from embryonic limb primordial cultures, indicating involvement of PKC? in embryonic osteogenesis, a role for PKC? in post-natal osteoblast function and the molecular targets of PKC? action in skeletal cells have not been established. Our lab has shown that PKC? regulates the Runx2 activity, one of the master regulators of osteogenesis, thereby presenting a possible mechanism by which PKC? can impact osteogenic differentiation. The central hypothesis of this grant application is that that PKC? is a critical factor in multiple signaling cascades that converge on Runx2 and promote osteogenesis and increased bone formation. There are two specific aims to address this hypothesis. (Specific Aim 1) To examine the effect of PKC? deficiency on osteoanabolic signaling downstream of multiple pro-osteogenic factors in vitro. (Specific Aim 2) To characterize the in vivo impact of loss of PKC? in the cells of the osteoblastic lineage on post-natal bone formation. Cell and molecular biology, as well as in vivo genetic models, will be used to resolve key knowledge gaps regarding the role of PKC? in bone. Defining these mechanisms will provide critical understanding into how PKC? ultimately affects osteoblast function and bone mass acquisition. Hopefully, the knowledge gleaned from these studies will aid in the development of rational therapies against low bone mass disorders that stimulate the formation of bone by targeting pathways that converge on Runx2 via PKC? modulation.

Public Health Relevance

This grant contains research that is concerned with diseases of low bone quality such as osteoporosis. The successful completion of this research could open up new possibilities for therapeutic intervention and treatment of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AR064673-03
Application #
8868942
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Alekel, D Lee
Project Start
2013-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Orthopedics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Buo, Atum M; Tomlinson, Ryan E; Eidelman, Eric R et al. (2017) Connexin43 and Runx2 Interact to Affect Cortical Bone Geometry, Skeletal Development, and Osteoblast and Osteoclast Function. J Bone Miner Res 32:1727-1738
Buo, Atum M; Williams, Mark S; Kerr, Jaclyn P et al. (2016) A cost-effective method to enhance adenoviral transduction of primary murine osteoblasts and bone marrow stromal cells. Bone Res 4:16021
Gupta, Aditi; Anderson, Hidayah; Buo, Atum M et al. (2016) Communication of cAMP by connexin43 gap junctions regulates osteoblast signaling and gene expression. Cell Signal 28:1048-57
Buo, Atum M; Stains, Joseph P (2014) Gap junctional regulation of signal transduction in bone cells. FEBS Lett 588:1315-21
Gupta, Aditi; Niger, Corinne; Buo, Atum M et al. (2014) Connexin43 enhances the expression of osteoarthritis-associated genes in synovial fibroblasts in culture. BMC Musculoskelet Disord 15:425