Rheumatoid arthritis is a chronic autoimmune disease with an
extensive inflammation of the synovial membrane results in erosions of articular
cartilage and marginal bone causing inflammatory joint destruction. Arthritis
is chiefly a disease of joints and is a pro inflammatory disorder, thus a full
understanding of the pro inflammatory character of arthritis is essential for
the success of therapeutic trials (Smolen JS, 2016.).

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Bone is primarily composed of support cells including osteocytes and
bone forming osteoblast; bone remodelling cells and non mineral matrix of
proteins called osteoid with inorganic mineral salts deposited in the matrix.
The main bone remodelers are osteoclasts, osteoblast, osteoprotegerin,
paracrine cell signalling and receptor activator of NF-?B. Excessive
formation of osteoclast causes diseases such as osteoporosis and rheumatoid
arthritis  (Basir S F, 2017).

The present molecular
biological technologies have extended useful approaches for RA research. Nowadays,
gene expression is used as a prime tool to investigate pathogenesis in RA and
provided useful information for understanding RA  (Burska AN, 2014;). RA susceptibility loci were discovered through candidate gene,
linkage, and genome-wide association studies. The gene signatures in the
synovial tissues of RA and osteoarthritis have been found using microarray
approaches (van der Pouw Kraan TC &
Breedveld FC, 2003;).  Lately, it is accepted
that NF-?B serves as a central inflammatory mediator that responds to a large
varieties of immune receptors signals. Since deregulated NF-?B activation is
involved in various inflammatory diseases, targeting the NF-?B signalling
pathway represents an attractive approach for anti-inflammatory therapies.
Several categories of inhibitors have been developed to block different steps
of NF-?B signalling (Ting Liu, 2017)





Arthritis is an endothelial dysfunction could be termed as a
systemic disorder underlying chronic inflammation in rheumatoid arthritis (Chimenti MS, 2015).

The role of chemokines and enzymes of inflammation such as
cyclooxygenase-2, 5-lipoxygenase and matrix metalloproteinase (MMP)-9,
interleukin (IL)-1b, IL-6, cytokines TNF- ? and adhesion molecules in the process of arthritis occurrence had been documented. Most of the inflammatory
mediators involved in arthritis have been studied and approved to be regulated
by nuclear factor-kB (Kumar A 2004) .

Rheumatoid arthritis, a chronic inflammatory disease of joint, is generated
by the complex interaction between genetic susceptibility and dysregulated
genes. The clinical manifestations of RA patients are the formation of pannus
and abnormal proliferative synovial tissue.

Early diagnosis could heighten the prognosis and the life quality
of RA patients. However, the pathogenetic mechanism of RA is indefinite and
there are no feasible biomarkers for early diagnosis in clinical practice (Hao, 2017).

The pathogenesis of RA involves a variety of cell types, including
innate immune cells such as monocytes / macrophages, T cells, B cells and
synovial fibroblasts. NF-?B mediates the induction of pro-inflammatory
cytokines, such as TNF-?, IL-1 and IL-6, in monocytes/ macrophages. The
canonical and non-canonical NF-?B pathways also mediate RANK ligand-induced
differentiation of monocytes/ macrophages into the bone-resorbing osteoclasts,
whose deregulation contributes to inflammatory bone loss associated with RA.(Baum R, 2016; )

In between the lymphocyte subsets of T cells, Th17 cells are predominantly
important for the pathogenesis of RA. NF-?B promotes Th17 differentiation both
indirectly through induction of inflammatory cytokines, IL-1, IL-6 and IL-23, of
cellular immune and directly regulates Th17 lineage transcription factors in T
cells (Teng MW, 2015;). Deregulated activation of
NF-?B also contributes to atypical survival of self-reactive B cells and autoantibodies
stimulation that contribute to the pathogenesis of RA (Wei F, 2015; ). Particularly, RA patients
often display elevated serum levels of B-cell activating factor belonging to
TNF family associated with unsynchronized activation of the NF-?B non-canonical
type. Therefore, NF-?B mediates the pathogenesis of RA by functioning in
different cell types as in figure 1 (Sellam J, 2010;).




Figure 1: Osteoarthritis pathophysiology
with involvement of the synovium. Products of cartilage breakdown released into
the synovial fluid are phagocytised by synovial cells, intensifying synovial
inflammation. In turn, production of proinflammatory mediators that leads to
excess production of the proteolytic enzymes responsible for cartilage
breakdown. In addition to the inflamed synovium contributes to the formation of
osteophytes via BMPs.


3. NF-?B mediator in rheumatoid


NF-kB is an initiator in the RA pathogenesis, and is essential to
the production of pro-inflammatory mediators in the inflamed synovium. However,
whilst much is known about the signalling pathways that result in NF-kB activation
in transformed cells and in lab animals, these events often differ in the cells
that are relevant to RA, such as primary human myeloid cells and cells of the
synovium. These events are only being fully explored now, using new
technologies such as adenoviral infection. Doubtlessly, cutting-edge
technologies, such as small inhibiting RNA, will also give great insights into
the functional roles of these proteins in prospect studies. This will be important
to help identify new therapeutic targets for the treatment of RA and validate
those therapies already underdevelopment. The exquisitely specific NF-kB
response induced by different stimuli in different cells gives hope that
treatments can be developed to specifically target NF-kB in the inflamed synovium
without detrimental effects on the innate immune system  (Foxwell B, 1998;). 

In the synovial cells with RA, activation of NF-kB pathway results
in the transactivation of a responsive genes that contribute to the
inflammatory phenotype, including TNF-a from macrophages, matrix metalloproteinases from synovial
fibroblasts and chemokines that hire immune cells to the inflamed pannus. This
is largely a consequence of activation of the ‘canonical’ NF-kB pathway that
involves heterodimers of p50/p65. Whilst much information on the role of NF-kB
in inflammation has been assembled from genetic deficiency of the respective
genes in mice, important differences exist in the signalling networks between
human and murine immune cells and immortalized cell lines. Despite these
differences at the molecular level, the importance of NF-kB in inflammation is approved
and inhibition of the pathway is widely believed to have great potential as a
therapeutic target in RA. Commercial effort has exerted into developing
inhibitors of NF-kB activation. However, inactivation of the NF-kB can result
in an exacerbation of inflammation if TNF-a production by macrophages is not controlled. It will be important
that such inhibitors are carefully monitored before their long-term use in chronic
inflammatory conditions of RA (Perkins, 2007;). 

The data gained from RA patients suggests NF-?B activation is thoroughly
involved in the chronic inflammation of the RA synovium. Accordingly,
inhibitors of NF-?B are potential approach as therapeutics for RA. The successful
trials for treatments that directly target the products of NF-?B focused genes,
such as TNF-?, IL-6 and IL-1 has been a major advance in the treatment of RA
patients that do not respond to the pattern treatment (Sacre SM, 2005).


A useful escalating evidence that NF-?B is a major transcription
factor controlling inflammation. The activation of the NF-kB pathway is concerned
in the pathogenesis of chronic inflammatory disorders, including rheumatoid
arthritis and inflammatory disease of bowel (Hayden, 2012.). NF-kB proteins are regulated by an inhibitor of NF-kB kinase (IkB)
complex formed by NF-k kinase inhibitor (IKK) and IKKb and subunit IKKg which
is a regulatory. This inhibitor kinase phosphorylates IkB, which is
subsequently ubiquitinated and degraded, leading to the activation of NF-kB (Harton, 2002. ; Oeckinghaus,
2011.). Moreover, several members of the nucleotide-binding domain and
leucine-rich repeat containing (NLR) family including NOD1, NOD2, NLR pyrin
domain containing (NLRP)3, and NLRP2 regulate the activation process of NF-kB (Fontalba, 2007. ). A common signalling event is activation of the canonical NF-?B
pathway, which is responsible for transcriptional induction of pro-inflammatory
cytokines, chemokines and additional inflammatory mediators in different types
of innate immune cells (figure 2) (Hayden MS, 2011; ; Sun SC, 2013; ).