Happy Holidays!

Role of p21 in RA and agents that modulate it

Recent Science News announcement on p21 “bouncer” protein raised questions in our readers—is p21 unique to RA? Do any herbs or supplements modulate its activity?

Let’s discuss the role of p21 first. Most cells in our bodies can grow and replicate. The full process of one cell making 2 cells is termed cell division and involves progression of the cycle.

Many cells remain resting because there are enough of them to perform their function. For example, the cells that make up the membrane in the knee and shoulder joints is very thin and is called the synovial membrane. The synovial membrane is just a few cell layers thick.

However, during the onset of RA, some cause triggers the cells of the synovial membrane to begin growing. A thickened membrane is called pannus. In order for the synovial cells to proliferate or make more, they need to go through cell cycle progression.

p21 blocks progression of the cell cycle by several mechanisms.

First, it inhibits the activity of cell cycle dependent kinases. Proteins involved in DNA replication are not made.

Second, p21 also protects against cell death (apoptosis). p21 halts cell cycle progression which protects against cell death. p21 also binds to and blocks several proteins directly involved in apoptosis (procaspase 3, caspase 8, caspase 10).

Surprisingly, under some conditions, p21 may also promote apoptosis.

Thus, modulating p21’s activity to improve health is expected to be challenging.

P21 is present in most cells and regulates cell cycle progression and apoptosis. Under some conditions, p21 can promote apoptosis rather than inhibit it. It helps maintain hematopoietic stem cells, which make red and white blood cells throughout life.

A recent report in Arthritis and Rheumatism [1] described sustained arthritis and articular destruction in mice that lacked p21. Macrophages played a major role in the arthritis.

In the next few years, there will be several compounds that will boost p21 levels. Because p21 is an inhibitor of cell growth, any p21 stimulant may have side effects related to p21 function. Several medications used in treatment for RA also affect cell growth including methotrexate, and azathioprine. However, they do not directly act on p21.

Cyclosporine and tacrolimus increase the levels of p21 in lymphocytes [2, 3] as well as lowering production of important cytokines like IL-2. Cyclosporine is sometimes used to treat severe rheumatoid arthritis patients on a short term basis because of its side effects.

Laboratory studies suggest that melatonin modestly reduces proliferation of fibroblast-like synoviocytes from RA patients [4]. Melatonin is produced by the pineal gland.

Getting at least 5-10 min of sun on your forehead may boost your melatonin levels.

Curcumin, one of the main components of turmeric and curry spice, increases the expression of p21. However, curcumin also affects expression of many proteins involved in cell growth (Bcl-2, Bcl-XL, cyclin, c-myc, caspases 3, 8, 9, p53, DR4, DR5) [5].

Foods seasoned with curry may help reduce inflammation. Several models suggest that curcumin or curry may be beneficial in reducing inflammation [6, 7]. However, curry or curcumin is not well absorbed.

Each body is unique and its responses to all drugs, herbs, supplements, are not yet predictable. Thus, this is for information purposes only and each person is strongly encouraged to discuss any potential change with their personal physician.

The next issue we'll discuss 5 habits and environmental substances that can contribute to morning stiffness and suggestions to minimize or resolve their effects.

Wishing you very Healthy Happy Holidays!

Here’s to your healing,

Kathy Katherine Molnar-Kimber, Ph.D.


1. Mavers, M., et al., The cyclin dependent kinase inhibitor p21 is essential for resolution of murine inflammatory arthritis via its c-terminal domain. Arthritis Rheum, 2011.

2. Khanna, A.K. and J.D. Hosenpud, Cyclosporine induces the expression of the cyclin inhibitor p21. Transplantation, 1999. 67(9): p. 1262-8.

3. Khanna, A.K., The immunosuppressive agent tacrolimus induces p21WAF/CIP1WAF1/CIP1 via TGF-beta secretion. Biochemical and biophysical research communications, 2003. 303(1): p. 266-72.

4. Nah, S.S., et al., Melatonin inhibits human fibroblast-like synoviocyte proliferation via extracellular signal-regulated protein kinase/P21(CIP1)/P27(KIP1) pathways. J Pineal Res, 2009. 47(1): p. 70-4.

5. Ravindran, J., S. Prasad, and B.B. Aggarwal, Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? The AAPS journal, 2009. 11(3): p. 495-510.

6. Aggarwal, B.B., et al., Curcumin: the Indian solid gold. Advances in experimental medicine and biology, 2007. 595: p. 1-75.

7. Jackson, J.K., et al., The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis. Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2006. 55(4): p. 168-75.