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The Not-So-Odd Couple—The Clinician and the Experimentalist

Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas 77030

Address correspondence and requests for reprints to: Gerard Karsenty, M.D., Ph.D., Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030.

	Do clinicians and experimentalists need each other?

Top Do clinicians and... Control and common control... References

 
No one should forget that clinical medicine is an exceptionally hard job. It is not only hard but it can also be extremely frustrating because the goal is, by definition, repetitive: to cure the same disease day in and day out. Most often this must be accomplished promptly, to the expense of the true intellectual pleasure to elucidate how the disease observed develops. The impression of performing a routine job may dampen enthusiasm of physicians over time and also the prestige of the profession for outsiders. Indeed, the necessity to achieve primarily a cure, or at least a satisfactory treatment of any disease, may be perceived for the wrong reason by uninformed experimentalists as a lack of intellectual curiosity. This is forgetting that for every profession there is a first line of duty. For clinicians it is to cure first and to understand second. For experimentalists it is to understand first and only second to cure, or "rescue" as one says in the world of animal experimentation. And this is not easy either. These totally symmetrical goals and the enormous amount of work they both require daily explain, for the most part, the apparent difficulties sometimes observed in the necessary communication between clinicians and experimentalists. This dialogue is necessary because their two goals are complementary if not identical. Nothing comes easy in either profession, and, to a large extent, clinicians and experimentalists should be both viewed as scientists—they both practice biology, only under a different form. It is in this spirit that the dialogue between clinicians and experimentalists can develop. Beyond the cat and dog superficial aspect that the obligatory relationship between clinician and experimentalist sometimes adopts lies the real nature of their relation and why it is a lasting one: there is no biology without clinical validation at one point or another. Likewise, there is no progress in clinical medicine without animal experimentation.

Animal experimentation has a more profound influence than ever before on the way clinicians think, for at least two reasons. First, unlike what was the case until 10 yr ago, animals are not used anymore for pharmacologic experiments but to understand the biology as one can now dissect a genetic cascade, one mutant mouse after another. Moreover, genetic manipulations allow one to perform physiologic experiments at the molecular level in the entire animal, a feat that could not have been achieved before. The second reason explaining why the mouse has become such an important model for biology and medicine is the overall reproducibility of the observation made in mice when it comes to pathology. This is why clinicians cannot afford to ignore the findings of the mouse genetic field. Importantly, this does not apply only to developmental syndrome(s) but also to the elucidation of the molecular basis of acquired, late onset, degenerative disease(s). Conversely, mouse geneticists cannot afford to ignore the challenge facing the clinicians as they are often in a privileged, if not the best, situation to solve them. This is because the constant and sometimes unnoticed dialogue between clinicians and experimentalists is never interrupted that biology is making progress and will continue to do so. These statements do not reflect the viewpoint of an experimentalist but rather the one of a former clinician who, as an experimentalist, measures the wealth of information that resides at both ends of this dialogue provided that both sides listen to, or at least hear, each other. In short, assuming or believing that biologists and clinicians are not asking the same question is not an illusion, it is a delusion.

	Control and common control of bone formation and body weight

Top Do clinicians and... Control and common control... References

 
Two observations that could only come from clinical medicine are at the origin of a new line of research in bone biology and osteoporosis research. Conversely, this line of research could only be conducted in animals. The clinical observations are that gonadal function favors bone loss and that obesity protects from bone loss (1, 2, 3, 4, 5). Those two observations are true in every population studied. In molecular terms this was viewed as suggesting that body weight, reproduction, and bone remodeling share one or several common endocrine regulators. Given the neuroendocrine nature of the control of body weight and of reproduction a corollary of this hypothesis is that the control of bone remodeling could also be of neuroendocrine nature. As is the case for every hypothesis, whether it was wrong or right did not matter as much as the fact that it was testable in the entire animal. The test of this hypothesis led after many vicissitudes to the identification of leptin, a hormone that precisely controls body weight and reproduction, as the most potent inhibitor of bone formation identified to date. This also led to the demonstration that there was a neuroendocrine control of bone mass as infusion of leptin in the third ventricle of ob/ob or wild-type mice led to a decrease of bone mass (6). The central control of bone remodeling was shortly thereafter shown not to be restricted to leptin because it was shown that obese patients with an inactivating mutation in the melanocortin receptor 4 gene (MCR-4) have a higher bone mass than obese control individuals (7). Obviously, additional experiments are needed to understand, and possibly to use therapeutically, all the subtleties of this emerging concept of a central control of bone remodeling.

The two studies mentioned above were analyzing animals or patients that were obese. In this issue of JCEM, the study by Pasco et al. (8) goes one step further, in the same direction. Indeed, it shows that the level of serum leptin correlates, to a certain extent, with the bone mass of nonobese women when using a noninvasive method to measure bone mass. This is, in fact, in agreement with the observation that leptin-deficient mice have a high bone mass phenotype before they become obese. The study is, in fact, an eloquent example of how clinical medicine feeds animal experimentation, and vice versa. The differences observed between the group of women analyzed are small, yet this is still an important finding because it strengthens and broadens the role of leptin in the control bone mass to nonobese people. It also postulates that serum leptin is a predictor of bone mass. This, as well as several other points raised in the discussion of this interesting study, will need to be established more firmly in the future. It is likely that other studies, clinical and experimental, will continue to explore the role and mechanism of action of leptin on bone remodeling. More precisely, the underlying questions, beyond this clinical work and the previous one in rodents, are to know which structure in the hypothalamus responds to leptin input to control bone formation, what type of signals are sent by this putative bone remodeling center and which route does this downstream mediator(s) use(s) to affect bone formation so powerfully throughout the skeleton. The first answers to these questions will most likely not come from clinical investigations but rather from other animal studies. Yet, they will eventually receive their ultimate validation from clinical studies.

The long-term goal for this line of research, clinical and experimental, is eventually to shed a more molecular and mechanistic light to osteoporosis. This may lead to a novel bone-forming therapeutic for the disease. This, in my opinion, matters because we are still looking for such therapies. If this is the case, this line of research will illustrate in the most productive way how biology relies on the synergy between clinical and molecular investigations to thrive. Beyond biology itself there is the reasonable hope that this dialogue may change our therapeutic approach to osteoporosis. The study by Pasco et al. (8), by acknowledging the importance of leptin in the control of bone mass, pays tribute to the usefulness of the dialogue between clinical medicine and animal experimentation. It is the task of each of us to foster an even more productive dialogue.

Received March 12, 2001.

Accepted March 12, 2001.

	References

Top Do clinicians and... Control and common control... References

 

1. Riggs BL, Melton LJI. 1986 Medical progress: involutional osteoporosis. N Engl J Med. 314:1676–1686.[Medline]
2. Riggs B, Khosla S III MJ. 1998 A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. 13:763–773.[CrossRef][Medline]
3. Felson DT, Zhang Y, Hannan MT, Anderson JJ. 1993 Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res. 8:567–573.[Medline]
4. Tremollieres FA, Pouilles JM, Ribot C. 1993 Vertebral post-menopausal bone loss is reduced in overweight women: a longitudinal study in 155 early postmenopausal women. J Clin Endocrinol Metab. 77:683–686.[Abstract]
5. Ravn P, Cizza G, Bjarnason NH, et al. 1999 Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. J Bone Miner Res. 14:1622–1627.[CrossRef][Medline]
6. Ducy P, Amling M, Takeda S, et al. 2000 Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 100:197–207.[CrossRef][Medline]
7. Farooqi IS, Yeo GS, Keogh JM, et al. 2000 Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. 2:271–279.
8. Pasco JA, Henry MJ, Kotowicz MA, et al. 2001 Serum leptin levels are associated with bone mass in non-obese women. J Clin Endocrinol Metab. 86:1884–1887.[Abstract/Free Full Text]

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