(The molecular conductors of the inflammatory orchestra)

Transcription is the term that scientists use to describe the initial steps utilizing the cells genetic material, DNA, to make proteins. Just like verbs are the action words of sentences, proteins are the action molecules of the cell. Proteins make things happen, both good and bad. Transcription factors are those molecules that activate DNA to start the process of making protein messengers. Activate the DNA in the area coding inflammatory molecules and you get inflammation. Thats what we are trying to balance. There are several transcription factors that are important for joint health including: NFkB- Nuclear Factor kappa Beta SAF-1- Serum Amyloid A- Activating Factor 1 SOX- Sry-related HMG box Nfat- Nuclear factor of activated T cells I know what you are thinking, OMG! Hes got to be kidding me. Im not kidding. Dont worry about the particulars. I want you to follow that there is a significant scientific basis behind The Healthy Joints for Life Program. Stay calm and youll see where this follows. NFkB is the main transcription factor that we are trying to balance or subdue in our quest to fight inflammation. NFkB is inactive in the cell until something activates it. The pathways to activate NFkB are quite complex as this diagram shows.

The Transcription Factors

What we need to know is that oxidative stress, infections, various inflammatory proteins like interleukins, and tumor necrosis factor as well as insulin, other hormones and growth factors can all activate NFkB. When NFkB is activated it turns on the DNA in the area where inflammatory molecules like matrix metalloproteinases, tumor necrosis factor, IL-1B and COX enzyme are made. The production of these molecules leads to an inflammatory response and an escalation of production of additional inflammatory molecules. This is not good if you are trying to fight joint pain. One of the prime considerations of The Healthy Joints for Life Program is balancing NFkB. Notice I said balancing and not blocking NFkB because it does have important functions in the cells including those involved in fighting infection. If we can find a happy balance of NFkB then we will see some reduction in inflammation and joint pain relief. The SAF-1 transcription factor works in both joint-lining cells (called synoviocytes) as well as cartilage cells (called chondrocytes). SAF-1 works in conjunction with AP1 to regulate matrix metalloproteinases, the proteins that aggressively digest cartilage components and VEGF which is a protein messenger responsible for the formation of bone spurs and other bone effects. The SOX family of transcription factors are master regulators of cartilage development. Specifically SOX activates genes for cartilage extracellulatr matrix component aggrecan. I am excited about this last transcription factor, Nfat 1. Its involvement in cartilage health is complex. In one study Nfat increased production of TNF alpha as well as matrix metalloproteinases yet almost in contradiction another study showed that lack of this transcription factor led to loss of type 2 collagen (the most important collagen in the articular cartilage that caps the bone), increased production of inflammatory cytokines, spur formation, bone thickening and cartilage cell proliferation and clumping. Lack of Nfat appears to be related to all the characteristic of osteoarthritis. While we know a considerable amount about balancing NFkB we know much less about SAF-1, SOX and Nfat-1. Our ultimate goal will be to have a more thorough understanding of all these transcription factors, how they relate to one another and how to balance them.

The following is a brief bibliography.

NFkB
Baldwin AS. Series Introduction: The transcription factor NF-kB and human disease, J. Clin Invest. 2001 January 1; 107(1):3-6. Checker, R. "Potent anti-inflammatory activity of ursolic acid, a triterpenoid antioxidant, is mediated through suppression of NF-KB, AP-1 and NF- AT.." PLoS One. 7.2 (2012): e31318. Chen F, Castranova V, Shi X, Demers LM. New insights into the role of nuclear factor- kappaB, a ubiquitous transcription factor in the initiation of diseases, Clin Chem. 1999 Jan;45(1):7-17. Chung HY, Kim HJ, Kim JW, Yu BP. The inflammation hypothesis of aging: molecular modulation by calorie restriction, Ann NY Acad Sci. 2001 Pri; 928:327-35. Csisar A, Wang M, Lakatta EG, Ungvari Z. Inflammation and endothelial dysfunction during aging: role of NF-Kb, J Appl Physiol. 2008 105:1333-1341. Kakkar P, Singh BK. Mitochondria: a hub of redox activities and cellular distress control, Mol Cell Biochem. 2007 Nov;305(1-2):235-53. Epub 2007 Jun 12. Karin M, Lin A. NF-kappa.B at the crossroads of life and death, Nature Immunology (2002), 3(3), 221-227. Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor-kappaB: its role in health and disease, J Mol Med. 2004 Jul;82(7):434-48. Kundu JK, Surh YJ. Inflammation: gearing the journey to cancer, Mutat Res. 2008 Jul-Aug;659(1-2):15-30. Li Q, Withoff S, Verma IM. Inflammation-associated cancer: NF-kappaB is the lynchpin, Trends Immunol. 2005 Jun;26(6):318-25. Porta C, Larghi P, Rimoldi M, Totaro MG, Allavena P, Mantovani A, Sica A. Cellular and molecular pathways linking inflammation and cancer, Immunobiology. 2009 214(9-10):761-77.

SAF-1
Kumar, D. "Transcriptional synergy mediated by SAF-1 and AP-1: critical role of Nterminal polyalanine and two zinc finger domains of SAF-1.." J Biol Chem.. 284.3 (2009): 1853-62.

Ray, A. "An inflammation-responsive transcription factor in the pathophysiology of osteoarthritis.." Biorheology. 45.3-4 (2008): 399-409. Ray BK, Shakya A, Ray A. Vascular endothelial growth factor expression in arthritic joint is regulated by SAF-1 transcription factor. J Immunol. 2007 Feb 1;178(3):1774-82. Ray A, Bal BS, Ray BK. Transcriptional induction of matrix metalloproteinase-9 in the chondrocyte and synoviocyte cells is regulated via a novel mechanism: evidence for functional cooperation between serum amyloid A-activating factor-1 and AP-1. J Immunol. 2005 Sep 15;175(6):4039-48.

SOX
Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Cruombrugghe B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6, Genes Dev. 2002, 16: 2813-2828. Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B. Interactions between Sox9 and beta-catenin control chondrocyte differentiation, Genes Dev. 2004 May 1;18(9):1072-87.

Nfat
Hogan, P. G. "Transcriptional regulation by calcium, calcineurin, and NFAT." Genes and Dev.. 17. (2003): 2205-2232. Rao, A. "Transcription factors of the NFAT family: regulation and function.." Annu Rev Immuno;.. 15. (1997): 707-47. Print. Rodova, M. "Nfat1 regulates adult articular chodrocyte function through its agedependent expression mediated by epigenetic histone methylation." J Bone Miner Res. 26.8 (2011): 1974-86. Print. Sun R1, Zhang B2, Chen L2, Sun J2. Role of nuclear factor of activated T cells 1 in the pathogenesis of osteoarthritis. Exp Ther Med. 2014 Jan;7(1):195-198. Epub 2013 Nov 7. Wang, J. "Transcriptional factor Nfat1 deficiency causes osteoarthritis through dysfunction of the adult articular chondrocytes." J Pathol. 19.2 (2009): 163-72. Print.