The Doctor Weighs In

By Dov Michaeli MD, Ph.D

Did this question ever bother you? This is a question that falls into the category of “gee, I never thought of that” or “stupid, everybody knows that arthritis involves joints” followed by the plaintive counter “yes (mom/dad/ Bill/ doc), by why”? Indeed why? This question actually did occupy me for many years during my research career. Alas, I had no answer. Now, when I read a report in Science, I slapped my forehead as if to say “but of course, why didn’t I think of it”? But I am not writing this as a confessional; the findings are important for any sufferer from this dread disease, whether in its severe and debilitating forms, or the mild one that is just occasionally bothersome.

What is a synovium?

The normal synovium is a thin membrane that lines a joint, like the knee or elbow, or finger. It looks like the white membrane under the shell of a chicken egg; and it is just as exciting. That is, until recently.

A closer examination of this “boring” thin membrane revealed that it consists of a lining layer that is only a few cells thick and a sublining layer that consists of loose connective tissue, like collagen. The lining layer contains cells that look like fibroblasts (these are cells found in the skin and their function is to make collagen, the major skin protein), and are called synovial cells ( synovicytes). It also contains macrophages. These are the scavenger cells whose function is to pick up the tissue debris left by the destructive inflammatory process. But paradoxically, they also secrete protein molecules called cytokines, which cause the inflammation. Thus, macrophages both cause inflammation and form the cleanup brigade after the damage is done. If there is such a thing as a hypocritical cell, this is it.

What happens in arthritis?

Before I disclose the secret, here is one more crucial fact: on their surface, synovial cells have a protein molecule called Cadherin 11. This molecule is responsible for the adherence (hence the name) of the synovial cells to each other, organizing themselves into the synovial tissue. Take away the cadherin and the cells become disorganized. Not only that: remove the cadherin, and induction of inflammation becomes very difficult. Conclusion: an organized synovial tissue is necessary for inflammation to occur. And cadherin 11 is responsible for keeping these cells organized.

This is new knowledge, and it opens a brand new way to treat rheumatoid arthritis.

How so?

Cadherin is a surface molecule, and therefore available for therapeutic intervention. Cadherin 11 is absolutely necessary for the propagation of the inflammatory response and for the joint damage that ensues. So its manipulation, for instance blocking it with a drug, would result in “insulating” the joint tissue from the destructive forces of inflammation. And given the new tools of drug development, synthesizing a tailor-made drug that would do just that should be a relatively simple affair.

But wait, wait, there is more

People who study the intimate molecular events that occur in solid tumors like stomach, or colon cancers have long known that cadherin on the surface of the tumor cells is important in some way in the development of the cancer, and in its metastatic spread. We also know that the inflammation that occurs around the tumor is instrumental in its spread. Can we “insulate” the tumor from the effect of inflammation, and hence inhibit the metastatic spread, by manipulating the tumor cadherin? We don’t know yet, but this arthritis study is very suggestive.

So there we are: from an esoteric surface molecule on a seemingly inert cell residing in a “boring” membrane, to arthritis and to cancer. Doesn’t science does work in wonderfully unexpected ways?