Wednesday, July 21, 2004

Thinking Outside the Box, part II

This one will be short.  Yesterday, I told the story of parallel fiber - Purkinje cell synapses, those little points in the cerebellum that are involved in fear memory.  This is contrary to the popular, oversimplified, view of the cerebellum as a part of the brain that is responsible for balance and coordination.  Today, I discuss briefly another unexpected finding in physiology, one that is completely counterintuitive. 

The acronym TSH  stands for Thyroid Stimulating Hormone.  This is a hormone secreted by the anterior part of the pituitary gland.  The classical understanding  of TSH is that it acts on the thyroid gland, causing it to secrete more thyroid hormone.  In yesterday's post, I said that everything in the body serves more than one function. 

This is old news by now, but it illustrates my point so well that I will mention it today.  In the October 17, 2003, issue of Cell,  there is an article about TSH:

TSH Is a Negative Regulator of Skeletal Remodeling
Etsuko Abe 1,2, Russell C. Marians 1, Wanqin Yu 1,2, Xue-Bin Wu 1,2, Takao Ando 1, Yanan Li 3, Jameel Iqbal 1,2, Leslie Eldeiry 1,2, Gopalan Rajendren 1,2, Harry C. Blair 3,4, Terry F. Davies 1, and Mone Zaidi *1,2

1Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 USA
2Veterans Affairs Medical Center, Bronx, NY 10463 USA
3Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213 USA
4Veterans Affairs Medical Center, Pittsburgh, PA 15213 USA

The established function of thyroid stimulating hormone (TSH) is to promote thyroid follicle development and hormone secretion. The osteoporosis associated with hyperthyroidism is traditionally viewed as a secondary consequence of altered thyroid function. We provide evidence for direct effects of TSH on both components of skeletal remodeling, osteoblastic bone formation, and osteoclastic bone resorption, mediated via the TSH receptor (TSHR) found on osteoblast and osteoclast precursors. Even a 50% reduction in TSHR expression produces profound osteoporosis (bone loss) together with focal osteosclerosis (localized bone formation). TSH inhibits osteoclast formation and survival by attenuating JNK/c-jun and NFκB signaling triggered in response to RANK-L and TNFα. TSH also inhibits osteoblast differentiation and type 1 collagen expression in a Runx-2- and osterix-independent manner by downregulating Wnt (LRP-5) and VEGF (Flk) signaling. These studies define a role for TSH as a single molecular switch in the independent control of both bone formation and resorption.

The neat thing about this finding is that it illustrates another general principle of physiology: most processes are regulated via two opposing forces.  In the case of bone growth, there are cells that build new bone, and cells that break down existing bone.  Both processes are active all the time.  If the buildup goes faster than the breakdown, the bone gets bigger, or more dense.  Low TSH levels result in the formation of both kinds of cell, but the formation of bone-destroying osteoclasts is faster than the formation of osteoblasts.  Therefore,  bone is broken down faster than it is built up.  Science News Online has a nice summary  of what was known about this in the year 2000. 

The finding that TSH regulates bone formation explains something that has long been known, but which previously was not understood.  Patients treated with excessive thyroid hormone are at risk for osteoporosis.  It now appears that the reason for this is that patients given large doses of thyroid hormone produce very little TSH.  It is not the thyroid hormone itself that causes bone loss; it is the suppression of TSH that does it. 

It still is a mystery, why the body would be set up this way. 

One can hope that this finding could lead to new approaches to treating osteoporosis: a common and debilitating condition, especially among elderly women.