Intellectual disability (ID) results from developmental conditions that are characterized by significant deficits in intellectual functioning with a prevalence of 1-3% in general population. In most cases, patients with ID also present with skeletal abnormalities. Recent studies identified several different nonsense mutations in the trafficking protein particle complex (TRAPPC9) gene in both consanguineous and non-consanguineous families. Patients with TRAPPC9 mutations share phenotypic features including unique facial appearance, skeletal abnormalities, moderate-to-severe ID, highlighting the importance of TRAPPC9 in both brain and skeletal development. However, its precise role in normal skeletogenesis remains obscure. TRAPPC9 is known as NIBP [NFkB inducing kinase (NIK) and IkB kinase 2 (IKK2) binding protein]. It enhances cytokine- induced NFkB activation by increasing the kinase activities of IKK2 and NIK, modulating both the canonical and non-canonical NFkB signaling. In addition, TRAPPC9 is also critical to intracellular vesicular trafficking. The relative importance of NFkB signaling and vesicular trafficking to the skeletal phenotype in TRAPPC9 patients is unknown. In this application, we propose to study the role of TRAPPC9 in normal bone physiology and its role in osteoclast (OC) differentiation and function. Our preliminary studies show that TRAPPC9 is expressed in bone cells and binds NIK and IKK2 in OC in vitro. Functional knockdown of TRAPPC9 in OC leads to defective OC differentiation and function. In addition, floxed-TRAPPC9 transgenic mice crossed with myeloid-specific Cre (LysM) mice, develop osteopetrosis. Together these results strongly suggest TRAPPC9 is a positive regulator of osteoclastogenesis. TRAPPC9 also mediates vesicular trafficking. Here we present data that TRAPPC9 binds to L-plastin and regulates actin-ring formation and OC function. These findings and others presented in this application, prompted us to hypothesize that TRAPPC9 regulates osteoclast differentiation and function via modulation of NFkB-dependent and unrelated signaling pathways. To test our hypothesis, we propose to examine the functional role of TRAPPC9 using conditional null mice in OC lineage. In addition, we will determine the mechanisms by which TRAPPC9 modulates NFkB-dependent signaling in OC.
Aim 1 will focus on characterization of the skeletal phenotype of TRAPPC9 conditional knockout mice and will examine the impact of TRAPPC9 deficiency on OC differentiation and function.
Aim 2 will elucidate the molecular mechanism by which TRAPPC9 regulates of NFkB signaling and determine the physiological role of TRAPPC9 in osteoporosis.
Aim 3 will examine the role of TRAPPC9 in OC polarization and function. In sum, these experiments will decipher the role of TRAPPC9 in regulating bone mass and the mechanisms by which TRAPPC9 regulates NFkB signaling. The successful accomplishment of this project will generate new clues to enhance our knowledge of NFkB signaling in bone cells and the development of therapeutic modalities for bone loss diseases.

Public Health Relevance

Osteoporosis is a major health care problem since approximately 10 million people over the age of 50 have been diagnosed with the disease and 33.6 million more are estimated to have low bone mass (osteopenia). TRAPPC9 is a novel protein in bone and the proposed studies will generate new information regarding its effects and mechanisms of action on bone cell development and function. Once we understand its full effects on bone and how it works to promote bone formation, this information will be helpful in developing new therapeutic strategies to selectively enhance bone formation in patients with clinically significant bone loss.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
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Nicks, Kristy
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Northeast Ohio Medical University
Anatomy/Cell Biology
Schools of Medicine
United States
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