Yousef Abu-Amer, Ph.D.

Orthopaedic Surgery
Cell Biology and Physiology

Molecular Cell Biology Program
Developmental, Regenerative and Stem Cell Biology Program

  • 314-362-0335

  • 314-362-8514

  • 314-362-0334

  • 822 Yalem, Barnes Jewish Hospital North


  • bone biology, signal transduction, osteoclast, TNF, NF-kB

  • Cellular and molecular mechanisms in osteoclasts; TNF signaling in inflammatory bone disease

Research Abstract:

Excessive osteoclast activity is the lead cause of bone loss in diseases such as osteoporosis, rheumatoid arthritis, and inflammatory osteolysis. Our laboratory is focused on investigating molecular mechanisms of osteoclast differentiation and activation under inflammatory conditions. These include identifying the molecular mechanisms of pro- and anti-inflammatory cytokine-regulation of osteoclastogenesis.

We have delineated a novel pro-osteoclastic signaling pathway transmitted by tumor necrosis factor alpha (TNF) via its type-1 receptor in osteoclast precursor cells. This pathway accelerates RANK\RANKL-mediated osteoclastogenesis in states of inflammatory insults to skeletal tissues.

Because TNF and RANKL signaling pathways in osteoclasts rely on activation of the transcription factor NF-kB and this factor is critical for differentiation of osteoclasts and bone homeostasis, we investigated critical steps that regulate NF-kB activation. In this regard, we have employed dominant-negative form of the NF-kB inhibitory protein, IkB, and blocked in vitro osteoclastogenesis and bone erosion in joints of arthritic animals. In another approach, we have targeted and inhibited activation of the IkB kinase (IKK) complex leading to attenuation of osteoclastogenesis and bone erosion.

We are also engaged in exploring molecular mechanisms of anti-inflammatory cytokines and their role as potent anti-osteoclastic agents. In this respect, we have established that the T-lymphocyte secreted interleukin-4 inhibits NF-kB activation and osteoclast formation. This process is dependent upon activation of another transcription factor termed STAT6 (signal transducer and activator of transcription 6) which in this case acts as a repressor of transcription. Thus, STAT6-based design is being investigated as a potential therapy for inflammatory bone loss.

Selected Publications:

Dai S, Hirayama T, Abbas S, Abu-Amer Y. The IKK inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis. J Biol Chem 2004 279:37219-37222.

Abbas S, Abu-Amer Y. Dominant-negative IkB facilitates apoptosis of osteoclasts by tumor necrosis factor. J Biol Chem 2003 278:20077-20082.

Abu-Amer Y. Mechanisms of inflammatory mediators in bone loss diseases. In: Rosier, R. N.; Evans, C. H., editors. Molecular biology in orthopaedics. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2003. p. 229-239.

Abu-Amer Y. Interleukin-4 abrogates osteoclastogenesis by mechanisms involving STAT6 inhibition of NF-kB transactivation. J Clin Invest 2001 107:1375-1385.

Abu-Amer Y, Dowdy SF, Zhang YH, et al. TAT fusion proteins containing tyrosine-42-deleted IkBa arrest osteoclastogenesis. J Biol Chem 2001 276:30499-30503.

Last Updated: 8/3/2011 12:50:26 PM

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