Defective bone remodeling is the pathophysiologic basis of most metabolic bone diseases, including postmenopausal and age-dependent osteoporosis. In previous work, we have found that osteoblasts express members of the cadherin superfamily of cell adhesion molecules, in particular cadherin-11 (Cad11) and N-cadherin (Ncad). Cadherins mediate cell-cell adhesion, but they also intersect the Wnt signaling pathway by stabilizing ?-catenin on the cell surface. Cell-cell adhesion is also a pre-requisite for assembly of gap junctions and intercellular communication. We have demonstrated that either dominant-negative disruption of cadherin function or recessive null mutations of the Ncad and/or Cad11 genes (Cdh2 and Cadh11) in mice hinders bone formation, leading to low peak bone mass and osteopenia. We also find that cadherin deficiency negatively affects the Wnt/?-catenin system and reduces the abundance of intercellular junctions (adherens and gap junctions), in vitro. The central hypothesis of this project is that cadherins (Ncad and Cad11) control osteogenic differentiation by modulating cell-cell interactions in the bone marrow microenvironment, via cell-cell adhesion, communication and signaling. We further hypothesize that Ncad and Cad11 have partially overlapping, yet distinct roles in the osteoblast differentiation program. To achieve this goal, we propose to determine, 1) the relative roles of Cdh2 and Cdh11 in bone forming cell commitment and differentiation and proliferation in the post-natal skeleton;2) the interactions between cadherins (Ncad and Cad11) and Wnt signaling in osteoblast differentiation and function and 3) cadherin dependent organization and function of intercellular junctions (adherens and gap junctions) in osteogenic differentiation. We will use multiple in vitro, ex vivo and in vivo approaches, based on cadherin gene ablation mouse models we have developed, to study the consequences of cadherin deficiency on bone development, bone mass and osteoprogenitor cell recruitment and differentiation. We will also determine the cellular and molecular bases of the osteopenia of cadherin deficient mice. This proposal addresses fundamental mechanisms by which bone turnover is modulated in the bone microenvironment. Understanding the role of cadherins in bone biology is essential to gain a full picture of the molecular network by which bone development and homeostasis are controlled.

Public Health Relevance

Therapeutic options for stimulating bone formation in subjects with bone demineralization, such as osteoporosis, are limited. This research will study two molecules that allow cells in the bone marrow and on the bone surface to come in direct contact, thus influencing each others' function and ability to manufacture new bone. Results will allow us to better understand how bone forming cells develop in adult animals, and will give us new tools to help people with low bone mass and fractures, by maximizing their potential for making new bone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055913-04
Application #
8291152
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Chen, Faye H
Project Start
2009-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$325,037
Indirect Cost
$111,197
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Revollo, Leila; Kading, Jacqueline; Jeong, Sung Yeop et al. (2015) N-cadherin restrains PTH activation of Lrp6/?-catenin signaling and osteoanabolic action. J Bone Miner Res 30:274-85
Marie, Pierre J; Hay, Eric; Modrowski, Dominique et al. (2014) Cadherin-mediated cell-cell adhesion and signaling in the skeleton. Calcif Tissue Int 94:46-54
Salazar, Valerie S; Zarkadis, Nicholas; Huang, Lisa et al. (2013) Embryonic ablation of osteoblast Smad4 interrupts matrix synthesis in response to canonical Wnt signaling and causes an osteogenesis-imperfecta-like phenotype. J Cell Sci 126:4974-84
Greenbaum, Adam M; Revollo, Leila D; Woloszynek, Jill R et al. (2012) N-cadherin in osteolineage cells is not required for maintenance of hematopoietic stem cells. Blood 120:295-302
Di Benedetto, Adriana; Watkins, Marcus; Grimston, Susan et al. (2010) N-cadherin and cadherin 11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms. J Cell Sci 123:2640-8