Alexis Nagel

The role of the dynamic O-GlcNAc modification in osteoblast differentiation and bone formation

Over 45 million men and women in the United States are afflicted with mild to severe bone loss (osteopenia and osteoporosis, respectively), leading to disruption of bone microarchitecture, increased skeletal fragility, and increased risk of fracture. Bone loss occurs when the net rate of bone formation by bone-forming osteoblasts (OB) is outpaced by that of bone-resorbing osteoclasts. In osteoporosis this phenomenon has been at least partially attributed to a reduction in the OB population. The dysregulation of bone turnover under conditions associated with altered glucose homeostasis, such as diabetes, suggests that bone formation is sensitive to changes in nutrient status, however the underlying mechanisms of this are not completely clear.

The reversible glycosylation of nucleocytoplasmic proteins by O-linked N-acetylglucosamine (O-GlcNAc) is a nutrient responsive post-translational modification (PTM) which regulates cellular signaling through dynamic interplay with phosphorylation. The actions of O-GlcNAc cycling enzymes O-GlcNAc transferase and O-GlcNAcase have been shown to affect epigenetic programs influencing cell fate decisions in multiple cell types, however the contribution of these two enzymes to OB activity and bone formation remains relatively unexplored. It was recently observed that the O-GlcNAc modification of the RUNX2 transcription factor enhanced binding to the OSE2 promoter region, suggesting a role for this PTM in OB function. To date we have identified 23 O-GlcNAc modified peptides in 7 day differentiated MC3T3E1 preOB by tandem MS/MS analysis of lysate fractions enriched for O-GlcNAc by WGA lectin weak affinity chromatography. Of particular interest is the elucidation of previously ambiguous O-GlcNAc modified sites on TGF-β activated kinase-1/MAP3K7 binding protein 2 (TAB2), a scaffolding protein implicated in cytokine signaling, nuclear co-repression, and osteo-adipo switching, and CREB-binding protein (CBP), an epigenetic regulator of developmental programs. Studies are underway to test the hypotheses that O-GlcNAc modification of transcriptional regulators such as RUNX2 and CBP, as well as signaling proteins such as TAB2, modulates OB development.

Mentor and Department

Peer Reviewed Manuscripts

Nagel, AK, H Kalariya, and G Schnabel (2010) The Gastrodia anti-fungal protein (GAFP-1) and its transcript are absent from scions of chimeric-grafted plum. HortScience. 45(2): 188-192

Nyczepir, AP, AK Nagel, and G Schnabel (2009) Host status of three transgenic plum lines to Mesocriconema xenoplax. HortScience. 44(7): 1932-1939

Nagel, AK, G Schnabel, R Scorza, and C Petri (2008) Generation and characterization of transgenic plum lines expressing the Gastrodia antifungal protein. HortScience. 43(5): 1514-1521

Relevant Published Abstracts

Nagel, AK, LN Waller, LE Ball (2011) The role of the nutrient-responsive O-GlcNAc modification of IRS-1 and 2 on insulin and IGF-1 signaling in osteoblasts. Experimental Biology Meeting. April 9-13, Washington, D.C., USA.

Nagel, AK, M Schilling, LN Waller, LE Ball (2012) Identification of proteins O-GlcNAc modified during osteogenesis. Experimental Biology Meeting. April 21-24, San Diego, CA, USA.