Yousef Abu-Amer, Ph.D.

J. Albert Key Professor
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

  • 11402 Institute of Health (IOH)


  • Musculoskeletal, inflammatory osteolysis, degenerative, bone biology, Signal transduction, NF-kB, Osteoclast, Bone Metabolism, Joint

  • Investigating molecular mechanisms underlying inflammation-induced degenerative skeletal diseases including joint degeneration, inflammatory arthritis and osteolysis

Research Abstract:

Our research interests are centered on investigating the molecular mechanisms underlying degenerative skeletal diseases such as inflammatory arthritis, joint degeneration, and osteolysis. Using tissue-specific gene deletions and expression approaches, we have delineated the role of various components of the transcription factor NF-kB family, including IKKbeta and NEMO/IKKgamma in skeletal development, joint and bone pathologies. Recently, we have developed NF-kB gain of function mouse models that mimic inflammation leading to tissue degeneration with specific focus on skeletal sites. These studies are geared toward identifying signal-specific targets to enable tissue-selective intervention to inhibit breakdown of skeletal elements and spare off-target effect.
We are also investigating the role of NF-kB as a link between intestinal inflammation and skeletal wasting as well as between synovial inflammation and joint destruction. Other aspects of ongoing research are focused on the role of NF-kB as central mediator of osteoimmunology (cross talk between the immune system and the skeleton).
Ongoing Projects:
- Title: Decoding NF-kB signaling in myeloid cells to decipher signal specificity. The fact that NF-kB is a ubiquitous transcription factor that mediates the function of numerous signals in all cell types in health and disease, limits its utility as a therapeutic approach. We have developed genetic mouse models to study stimulus-specific signaling signature with relevance to skeletal pathologies. The long-term goal is to decipher signal and cell-specific regulatory elements in the NF-kB system to permit precision of therapeutic intervention.
- Title: Molecular mechanisms underlying IKK complex in osteolysis and bone metabolism. This project utilizes gene knock out and knock-in approaches to investigate the role of IKKbeta in bone under normal and pathologic conditions.
- Title: NF-kB signaling is crucial for joint homeostasis. We are employing joint-specific (cartilage, synovium, etc) genetic and pharmacologic manipulation of key NF-kB components in the form of gain or loss of function, to better understand approaches to maintain joint health.
- Title: The role of TAK1 (activator of the IKK complex and MAP kinases) in skeletal development and pathologies. We are studying tissue-specific deletion of TAK1 at various stages of myeloid lineage development and its impact on skeletal development
- Title: Molecular mechanisms of NEMO/IKKgamma underlying bone health and disease. A NEMO-floxed mouse model is being used to delineate the role of this gene in bone tissue and examine its molecular contribution to bone pathologies with emphasis on particular domains essential for post-translational modification of this protein.
- Title: Systemic NF-kB dysregulation and its effect on skeletal development; a disease model. This project is aimed at studying the poorly defined impact of low grade systemic/chronic inflammation on bone health. Two models in which intestinal inflammation is established through intestine-specific expression of constitutively active IKKbeta or deletion of NEMO are being utilized.
- Title: Mutual regulation of NF-kB and FoxP3; osteoimmune mechanisms. This project utilizes appropriate gene knockout mice to investigate novel aspects of NF-kB contribution to the mechanism by which the forkhead transcription factor, FoxP3 (which is expressed by immune T reg cells), regulates bone homeostasis.
Title: Molecular mechanisms underlying orthopedic particle-induced osteolysis. We have discovered recently that orthopedic particles released from implants induce osteolysis through mechanisms involving poly-ubiquitination events. Our current research in this area utilizes relevant transgenic mice to elucidate these mechanisms. We are also investigating the mechanisms by which orthopedic particles evoke immune cells to exacerbate osteolysis

Selected Publications:

• Clohisy JC, Roy BC, Biondo C, Frazier E, Willis D, et al. Direct inhibition of NF-kappa B blocks bone erosion associated with inflammatory arthritis. J Immunol. 2003 Nov 15;171(10):5547-53. PubMed PMID: 14607962.
• Yamanaka Y, Karuppaiah K, Abu-Amer Y. Polyubiquitination events mediate polymethylmethacrylate (PMMA) particle activation of NF-kappaB pathway. J Biol Chem. 2011 Jul 8;286(27):23735-41. PubMed PMID: 21566132; PubMed Central PMCID: PMC3129154.
• Otero JE, Tim Chen, Kaihua Zhang, Yousef Abu-Amer. Constitutively active canonical NF-kB pathway induces severe bone loss in mice. PLoS ONE 2012; 7(6):e38694. PMID: 22685599. PMCID: PMC3369901

• Abu-Amer Y. NF-kB and bone resorption. Osteoporosis International 2013 (March 7). PMID: 2348073. PMC 3884829

• Cassel SL, Janczy JR, Bing X, Wilson SP, Olivier AK, Otero JE, Iwakura Y, Shayakhmetov DM, Bassuk AG, Abu-Amer Y, et al., Inflammasome-independent IL-1beta mediates auto-inflammatory disease in Pstpip2-deficient mice. Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1072-7. PMID: 24395802. PMC3903222

• Swarnkar G, Zhang K, Mbalaviele M, Long F, Abu-Amer Y. Constitutive Activation of NF-κB Impairs Osteogenesis 1 and Skeletal Development. PLoS ONE 2014; 9(3):e91421. doi: 10.1371/journal.pone.0091421, PMC3949987

• Swarnkar G, Karuppaiah K, Mbalaviele G, Chen T, Abu-Amer Y. Osteopetrosis in TAK1 deficient mice owing to defective NF-kB and NOTCH signaling. Proc. Natl. Acad. Sci USA. 2015 Jan 6;112(1):154-9. doi: 10.1073/pnas.1415213112. Epub 2014 Dec 22. PMC4291677

• Chen TH, Swarnkar G, Mbalaviele G, Abu-Amer Y. Myeloid lineage skewing due to exacerbated NF-kB signaling facilitates osteopenia in scurfy mice. Cell Death Dis. 2015 Apr 16; 6:e1723, PMID: 25880090; PubMed Central PMC4650554

• Swarnkar G, Shim K, Nasir A, Seehra K, Chen H, Mbalaviele G, Abu-Amer Y. Myeloid deletion of NEMO causes osteoporosis in mice owing to upregulation of transcriptional repressors. Nature Sci. Reports, 6:29896, PMID 27435916, PMC4951754

• Wei Zou, Nidhi Rohatgi, Timothy Hung-Po Chen, Joel Schilling, Yousef Abu-Amer, Steven L. Teitelbaum. PPARγ Regulates Pharmacological but not Physiological nor Pathological Osteoclast Formation. Nature Medicine, 2016 Nov 8;22(11):1203-1205. PMID:27824823

• Swarnkar G, Karuppaiah K, Abu-Amer Y. NUMBL Negatively Regulates NF-κB Signaling via Interaction with TAK1, TRAF6 During Osteoclastogenesis. Nature Sci Rep. 2017 Oct 3;7(1):12600. doi: 10.1038/s41598-017-12707-7. PMID:28974699

Last Updated: 2/16/2018 11:27:55 AM

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