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The role of lipids in osteoporosis

The fatty acid receptor GPR40 has been found on the membrane of bone cells involved in bone remodelling. When stimulated, it slows bone loss. This discovery opens new possibilities for therapeutic and nutritional treatments of osteoporosis.

Sponge-like structure formed by bone trabeculae, present in short bones and the extremity of long bones (epiphysis). In osteoporosis, this trabecular architecture gradually disappears,  weakening the bone, which can break at the slightest impact.. © Inserm
By Louise Bergès, translated by Teri Jones-Villeneuve
Updated on 10/02/2013
Published on 09/11/2013

Bone, made up of a mineralized matrix for rigidity and bone cells that maintain it, is a living tissue that continuously renews itself. Two types of specialised cells are involved in this renewal: osteoclasts, which break down old bone tissue, and osteoblasts, which form new bone tissue. This process is called bone remodelling.

Osteoporosis is a bone disease which weakens the skeleton. It affects more than 70% of women over the age of 80 and increases the risk of fractures (such as the very common broken hip). INSERM has even called it a public health issue. For this type of bone disease, which is not only age-related but also linked to metabolic disorders like obesity, devising preventive nutritional strategies is particularly important. Prevention focuses on optimising nutrient intake during childhood (sufficient calcium to build a reserve of bone mass) and respecting lifestyle hygiene principles (physical activity, discouraging smoking and alcoholism).

However, very few studies have looked into the impact of fatty acids on osteoporosis – that is, until researchers at INRA’s Clermont-Ferrand centre revealed the protective role of a fatty acid receptor on bone cell membranes. Yohann Wittrant from INRA’s Food, Skeleton and Metabolism team sheds light on this new area of research.

What do we actually know about this receptor?

Yohann Wittrant: The GPR40 fatty acid receptor plays a key role in protecting the skeleton by maintaining bone mineral density. Mice which have been genetically modified (1) to not express this receptor showed severe osteoporosis.

Mice without the GPR40 receptor showed a much more fragile bone structure than control subjects (left). Lower extremity of the femur.. © INRA
Mice without the GPR40 receptor showed a much more fragile bone structure than control subjects (left). Lower extremity of the femur. © INRA

GPR40 is found in many organs: on the membrane of pancreatic and digestive tract cells, and even on tongue cells. We have now also discovered it on the membrane of osteoclasts, the bone cells involved in bone remodelling. Previous studies have shown it on immune system cells. Bone and immune cells share certain cell precursors. There was a chance that GPR40 could also be found on the membranes of these two cell types – and that turned out to be the case.

GPR40 is a transmembrane protein receptor that emits a cellular signal when certain fatty acids bind to it (2). The reaction to this signal changes depending on the cells’ specialisation.

What signal is transmitted to the bone cells when the GPR40 is stimulated?

YW: We cultured bone marrow cells to isolate the osteoclast and their cell precursors. When these cells’ GPR40 receptors are stimulated, the cell differentiation by the osteoclasts is blocked. There is less bone resorption, which slows bone loss.

To demonstrate this, we used a receptor agonist. This particular compound, GW9508 (3) binds to the receptor and mimics the action of natural binders – long chain fatty acids. The addition of the agonist preserved the skeletons of the mice with severe osteoporosis, obtained classically by ablation of the genitalia (4).

This makes the GPR40 a preferred therapeutic and nutritional target. We are also interested in the signal it transmits via the osteoblasts, but the cell regulation path involved relies on more ambiguous mechanisms. This is what we are currently studying.

So, eating fattier food leads to more solid bones?

YW: Not at all! That’s exactly the kind of conclusion we’d like to avoid. We want to find a way to activate the GPR40 receptor while maintaining a healthy diet that is good for other organs. We wouldn’t want to start aggravating cardiovascular problems, for example. We have been hoping to find an omega-3 fatty acid (5) that would target only the receptor. But it’s too early at this stage to make any conclusions about our results. In addition, American researchers have shown that type 2 diabetes can be treated – or at least slowed – with another GPR40 agonist called AMG837.

For now, it appears that stimulating the GPR40 receptor not only has a protective effect on bone but positively affects other organs as well: it stimulates insulin secretion, aids neural differentiation and memory, affects taste and inhibits macrophage inflammation. It’s very encouraging today, that as life expectancy increases, we may be able to stay healthier longer.

(1) In these mice, the genetic sequence corresponding to the receptor was deleted at the embryonic stage.

(2) GPR40 is a G-protein-coupled transmembrane receptor (watch the video on how it works).

(3) GW9508 is a three-ring aromatic synthetic compound. It is the main GPR40 receptor agonist used in research.

(4) The procedure creates a deficiency in sex hormones, especially oestrogen, and causes bone loss.

(5) Omega-3 and omega-6 are essential polyunsaturated fatty acids. Omega-3 is found in fish and certain vegetable oils. These fatty acids are considered to be good for health, with some studies showing that they reduce cholesterol levels. Maintaining an optimal omega-6 to 3 ratio (set at 5:1 by ANSES; article in French) reduces the risk of obesity.

Contact(s)
Scientific contact(s):

Associated Division(s):
Nutrition, Chemical Food Safety and Consumer Behaviour
Associated Centre(s):
Auvergne Rhône-Alpes

Reference

Wauquier F, Philippe C, Léotoing L, Mercier S, Davicco MJ, Lebecque P, Guicheux J, Pilet P, Miot-Noirault E, Poitout V, Alquier T, Coxam V, Wittrant Y. 2013. The free fatty acid receptor GPR40 protects from bone loss through inhibition of osteoclast differentiation. J Biol Chem. Mar 1;288(9):6542-51. doi: 10.1074/jbc.M112.429084. Epub 2013 Jan 18