Arthritis Antibodies

Antibodies can be used to attack the signaling (TNF) molecule that mediates the autoimmune attack on arthritic joint tissues. These anti-TNF antibodies minimize inflammatory signaling, reduce joint inflammation and also reduce bone attrition.

Inflammation is an activated state of a tissue in which inflammatory cytokines, TNF, IL-1, IL-6 are secreted by T-cells and the tissue responds by expressing genes that cause characteristic vascular dilation and accumulation of migrating cells of the immune system. One particular type of blood cell, a macrophage, can also migrate to the site of inflammation and develop, in response to signals from the inflamed tissue and resident bone secreting cells, osteoblasts, into osteoclasts that degrade bone. Thus, inflammation of joints can result in bone destruction and increase in serum calcium.

TNF is particularly pivotal in the development of osteoclasts and bone destruction. Thus, drugs, such as thalidomide, that block TNF production, also block the symptoms of arthritis. Antibodies can also be developed that bind to TNF and some of these antibodies have been chemically and genetically modified to make them useful as drugs. Examples are Infliximab and Andalimumab. These are proteins that bind to and inactivate TNF. In a similar alternative strategy, a portion of the TNF receptor was engineer to serving as a neutralizing molecule to bind TNF in inflamed tissue. All of these TNF inactivators can reduce symptoms and provide effective therapy for arthritic joints.

The unanswered question in the use of TNF inactivators is, “What caused the inflammation of the joint in the first place?” Inactivation of TNF can provide a temporary return to approximately normal tissue function, but the symptoms are expected to return.

Thus, we come to the unifying question of what causes inflammatory disease mediated by the immune system and directed at normal tissue components. Two obvious candidates are diet and infectious agents.

Food ingredients can exacerbate or ameliorate the symptoms of inflammatory disease, and particular diets determine the risk of acquiring these diseases. Diet is a major factor in inflammation of any source. Bacterial or viral infections frequently precede inflammatory conditions.

The association of infection with inflammation remains controversial, but there is growing evidence that bacteria in particular reside in almost all inflamed tissues. Moreover, there is abundant anecdotal evidence of effective use of antibiotics in numerous inflammatory diseases, including arthritis, inflammatory bowel disease, atherosclerosis and cancers of various types.

I expect that elucidation of the link between chronic inflammation, diet and bacterial infection will provide increasingly effective and simple therapies for most diseases in the near future.

Cartilage as Rejuvenation

I have studied cartilage secreting (chondrocytes) for the last few years. Chondrocytes are normally derived by differentiation of mesenchymal stem cells (MSCs) that grow in the bone marrow. MSCs can differentiate to produce bone secreting cells (osteoblasts), muscle cells (myoctes), fat cells (adipocytes) and insulin-secreting cells (beta-pancreatic islet cells.) I chose to study a rat chondrosarcoma (RCS) cell line, because this is a type of cell that shares the properties of many other important cells and it will continue to grow in cell culture. Thus, I can dilute some RCS cells in a solution with all of the nutrients required for growth and the cells will stick to the surface of the plastic dishes that I use, grow and differentiate. If you stain the cultures for cartilage, you get the following micrograph.

At first the cells stretch out and move about the surface of the dish. Then they become progressively less adhesive to the surface and more spherical as they start to produce and secrete the polysaccharides (glycosaminoglycans, such as chondroitin sulfate and heparan sulfate) and proteins (collagen) of cartilage. Finally they produce thick layers of cells that are separated and embedded in cartilage. After a little more than a week in culture, the cells are moving through the cartilage matrix by enzymatically degrading the cartilage ahead of them and secreting new cartilage in their wake. The cells that eat their way to the dish surface separate the cartilage layer from the dish and the colonies of cells begin to slough off from the dish surface. Normal chondrocytes would eventually stop dividing under culture conditions, but the cancer line that I use continues to grow quite happily and can be diluted and plated continuously. Chondrocytes in cartilage live in cavities within the cartilage and are surrounded by heparan sulfate attached to proteins of their cell membranes, i.e. heparan sulfate proteoglycans.

Cut cartilage will grow back together as the chondrocytes mine, secrete and gradually knit the two surfaces together with strands of new cartilage. Movement through and renewal of cartilage, e.g. in the connective tissue of skin, is restricted if the collagen fibers that are assembled outside of the secreting cells are cross-linked. This is why sunbathing ages skin. High fructose corn syrup also accelerates cross-linking. This cross-linking is also what makes meat less tender. The cross-linking and toughness can be measured by inserting fluorescence-measuring probes into meat, because the protein cross-links fluoresce in UV light.

A consequence of the development of chondrocytes on the ends of bones, is that the nutrients for the cells change. Initially the chondrocytes enjoy the abundant glucose and oxygen of the blood stream and gradually they are remove further from blood vessels. (Note that cartilage actively inhibits vascularization, so there are no blood vessels in cartilage. This lack of blood vessels and associated enhanced risk of disfiguring infection, is a reason to discourage piercings that involve cartilage.) Chondrocytes snug in their little cartilage cavities no longer eat sugar or breath oxygen, they dine on cartilage and ferment.

What happens if you expose mature chondrocytes to a new source of rich nutrients? I think that the answer is rejuvenation. Quite literally, the chondrocytes regress and return to the lifestyle of their youth. Instead of producing mature, weight-bearing, dense cartilage, these rejuvenated cells start to produce the weaker matrix of their youth. This weak cartilage is readily damaged by abrasion and is not suitable for joint surfaces. This is one of the consequences of arthritis. Inflammation of cartilage brings rejuvenating, damaging nutrients to chondrocytes. The mechanical damage leads to destructive cycles of further inflammation.

Chondrocytes in cartilage also respond to mechanical stress and this stress maintains their maturity. Persistent weight bearing at the same orientation leads to bone production. Thus, after joint injury it is important to use the correct regimen of rehabilitation to maintain mobility of the joint and mineralization of the bone.

Osteoporosis Treatment

Osteoporosis is an imbalance between bone production and loss. Most loss is due to dietary use of omega-6 vegetable oils. Treatment should focus on elimination of demineralizing oils and minimizing inflammation.

It is hard for me to discuss osteoporosis without the image of Sally Field advocating the use of Boniva (the bisphosphonate Ibandronate, see figure) popping into my head. Advertising is very powerful. Bisphosphonates stop bone loss by killing osteoclasts, the cells that demineralize bone during bone remodeling.

Normally demineralization of bone by osteoclasts is followed by secretion of osteoid containing osteocalcin by osteoblasts. Osteocalcin initiates mineralization. Thus, a large fraction of bone is being rejuvenated by balanced osteoclast/osteoblast action at any given time. Cessation of this remodeling process in bone as in cartilage and other connective tissue, e.g. skin, gives the symptoms of aging.

Osteoporosis, loss of bone density, means that there is a net conversion of bone hydroxyapatite (calcium phosphate crystals) into blood calcium, followed by calcium loss in urine. This means that the continuing development and activity of osteoblasts and osteoclasts is out of control. Osteoblasts develop from stem cells that are also the origin of fat adipocytes. The transcription factor that controls the alternative destiny of these stem cells is PPARgamma. Omega-6 fatty acids are converted into molecules that stimulate PPARgamma and result in adipocyte production in bone marrow instead of osteoblasts. In general terms, vegetable oil (except olive oil) makes fat cells instead of bone cells.  This is particularly true in postmenopausal women.  It is no wonder that the emphasis on the use of vegetable oils to avoid saturated fats has resulted in a pandemic of osteoporosis.

Omega-3 fatty acids (fish oil) are anti-inflammatory and they do not stimulate the production of PPARgamma. As a consequence omega-3 fatty acids, DHA and EPA, enhance bone production and density, and are very important to maintain normal osteoblast production.

Osteoporosis treatments that block osteoclast development or activity can be expected to have long term side effects, because normal renewal of bone is being disrupted. Inhibiting bone demineralization can lead to a slowing of osteoporosis, but it does not get to the cause of the osteoporosis.

Because of the prevalence of diet-based chronic inflammation, one might expect that diet and lifestyle are also the foundation of most osteoporosis.  With both inflammation and osteoporosis vegetable oils appear to be the major culprit.  Aging is also associated with osteoporosis.  Most of the symptoms of aging can be attributed to mismanagement of chronic inflammation.  Now it turns out that osteoporosis is a dietary problem (vegetable oil) compounded by physical problems of inflammation that limit activity.  Loss of muscle mass, i.e. sarcopenia, and replacement with fat around organs and in bone marrow can be explained by diet-based chronic inflammation and inadequate weight-bearing exercise.

A major risk factor for osteoporosis is omega-6-rich vegetable oils, e.g. corn, soy, etc. In simple terms, the first step that I would recommend for anyone concerned about osteoporosis is to shift to an anti-inflammatory diet. Eliminate all vegetable oils, except olive oil, from the diet and supplement with omega-3 fish oils (short-chain omega-3 oils in most vegetable sources are much less effective.)

The biomedical literature is very clear. Osteoporosis is not normal, is not a part of aging and can be avoided. There are some genetic predispositions to osteoporosis, but most can be overcome by meaningful diet and lifestyle changes. An anti-inflammatory diet and lifestyle (sunlight for vitamin D and exercise) is the cheapest, safest and most effective way to prevent and treat osteoporosis.