NF-kappaB inhibition for rheumatoid arthritis and osteoporosis

Two studies suggest the value and importance of NF-kappaB inhibition in the treatment of rheumatoid arthritis and osteoporosis

The first publication:


RANKL/RANK as key factors for osteoclast development and bone loss in arthropathies

Summary of the abstract

Osteoporosis or rheumatoid arthritis are bone diseases affecting hundreds of millions of people worldwide. Ground-breaking discoveries made in basic science over the last decade shed light on the molecular mechanisms of bone metabolism and bone turnover.

Three molecules, the receptor activator of NF-kappaB (RANK), its ligand (the thing that binds to and activates it) and the decoy receptor (the thing that inhibits it – keeps it from being turned on), have been a major focus of scientists and pharmaceutical companies alike, since experiments using mice in which these genes have been inactivated unanimously established their pivotal role as central regulators of osteoclast function. (Really good things happen when this is blocked.)

Consequently, novel drugs specifically targeting RANK-RANKL and their signaling pathways in osteoclasts are expected to revolutionize the treatment ofvarious bone diseases, such as cancer metastases, osteoporosis, or arthropathies.


Inhibition of NF-kB, by inhibiting the RANK pathway that turns it on, might have an enormous, beneficial impact on the treatment of rheumatoid arthritis and osteoporosis

The authors appear enthusiastic about the possibility of inhibiting NF-kB and how that might revolutionize treatment for hundreds of millions of people worldwide.

I share their enthusiasm.

The second publication:

J Biol Chem. 2007 Jun 22;282(25):18245-53.

NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1

Summary of the abstract or free full text publication

Postmenopausal osteoporosis and rheumatoid joint destruction result from increased osteoclast formation and bone resorption induced by receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor (TNF).

Osteoclast formation induced by these cytokines requires NF-kappaB p50 and p52, c-Fos, and NFATc1 expression in osteoclast precursors.

The relationship between NF-kappaB and these other transcription factors in osteoclastogenesis remains poorly understood.

We conclude that NF-kappaB controls early osteoclast differentiation from precursors induced directly by RANKL and TNF, leading to activation of c-Fos followed by NFATc1.

Inhibition of NF-kappaB should prevent RANKL- and TNF-induced bone resorption.


Rheumatic joint destruction results from increased osteoclast formation that should be prevented by NF-kB inhibition

These authors sought to determine which transcription factors were really important. Their conclusion is that everything is controlled by NF-kB – that it is the Master Switch controlling joint destruction in rheumatoid arthritis.

Therefore the inhibition of NF-kB should prevent, or at least could prevent, joint destruction in rheumatoid arthritis.

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