Historical Reflections and the Future

IAIN MACINTYRE

William Harvey Research Institute, Barts and The London, Queen MaryUniversity of London, Charterhouse Square, London, United Kingdom

ABSTRACT: This meeting has excitingly described the modern status ofskeletal biology. Many advances are described in detail but it may be ofvalue to describe the original discovery of two iconic osteoclast regula-tors, calcitonin and PTH, whose development in the 1960s initiated therevolution in the field.

KEYWORDS: osteoblast; calcitonin; PTH

John Potts has already described the exciting history of PTH, crowned bythe secure demonstration that PTH administered intermittently has a markedanabolic effect on the skeleton especially evident in established osteoporosis—the first demonstration that osteoporosis is reversible.

Calcitonin was also discovered in the 1960s. Harold Copp1 carried out com-plex thyroparathyroid perfusions in the dog, which suggested that a calcium-lowering substance was being released. Mistakenly, but understandably, it waspresumed to originate from the parathyroid gland already the site of onecalcium-regulating hormone, PTH. The existence of calcitonin was quicklyconfirmed2 by a different technique of thyroparathyroid perfusion. Soon Mun-son and colleagues3 questioned the parathyroid origin in the serendipitousobservation that thyroid cautery in the rat could apparently release an agentresembling the postulated calcitonin in its calcium-lowering effects.

But a definitive demonstration that calcitonin was actually secreted by thethyroid was conclusive4 and identified calcitonin as a thyroid hormone.

But uncertainty still persists to the present day about the physiological roleof calcitonin as a calcium-regulating hormone. Knockout experiments of thecalcitonin and calcitonin receptor genes in the mouse quite unexpectedly pro-duced enhanced osteoblastic activity—a contradiction probably resolved byfurther ingenious mouse knockout experiments from Karsenty.5 He showedthat calcitonin gene knockout or calcitonin gene receptor knockout enhancedosteoblastic activity.

So it seems that calcitonin has an easily demonstrable osteoclast inhibitoryeffect strikingly evident after acute single administration. Such short-term

Address for correspondence: Iain MacIntyre, William Harvey Research Institute, Barts and theLondon, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ. Voice: 0207352 3355.

hhw046@mac.com

Ann. N.Y. Acad. Sci. 1117: xx–xxi (2007). C© 2007 New York Academy of Sciences.doi: 10.1196/annals.1402.079

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experiments were not capable of showing an osteoblast effect. However, it nowseems that calcitonin in vivo chronically produces a partial osteoblastic inhibi-tion together with its acute osteoclastic effect. The osteoblastic effect is likelydue to an early effect on a calcitonin osteoblast receptor similar to that seenin the osteoblast cell line (U20S) or alternatively due to an osteoclastic signalto the osteoblast (still to be discovered) completing the osteoblast–osteoclastpartnership discovered by Jack Martin and Gideon Rodan. But further com-plications remain: calcitonin turns out to have a profound anti-inflammatoryaction in experimental arthritis.6 There are obviously potential therapeuticpossibilities in these new findings.

There is no reason to expect that different branches of science will advanceat the same speed and in comparison with physics and molecular biology,skeletal biology, despite its recent exciting activity, needs further progress tomatch that in other branches of science. Thus, the delightful idiosyncraticRichard Feynman with his seminal development of quantum electrodynamics,and the preposterously knowledgeable Murray Gell-Man with his predictionand demonstration of the quark still await their creative peers in our own area.

Author’s Note: The recent article from Karsenty (Cell 130, 456–469, [2007])may well mark the needed revolutionary finding in the fields of physiologyand skeletal biology.

REFERENCES

1. COPP, D.H., E.C. CAMERON, B.A. CHENEY, et al. 1962. Evidence for calcitonin—anew hormone from the parathyroid that lowers blood calcium. Endocrinology 70:638–649.

2. KUMAR, M.A., G.V. FOSTER & I. MACINTYRE. 1963. Further evidence for calcitonin,a rapid-acting hormone which lowers plasma-calcium. Lancet ii: 480–482.

3. HIRSCH, P.F., G. GAUTHIER & P.L. MUNSON. 1963. Thyroid hypocalcemic principleand recurrent laryngeal nerve injury as factors affecting the response to parathy-roidectomy in rats. Endocrinology 73: 244–252.

4. FOSTER, G.V., A. BAGHDIANTZ, M.A. KUMAR, et al. 1964. Thyroid origin of calci-tonin. Nature 202: 1303–1305.

5. DACQUIN, R., R.A. DAVEY, C. LAPLACE, et al. 2004. Amylin inhibits bone resorptionwhile the calcitonin receptor controls bone formation in vivo. J. Cell Biol. 164:509–514.

6. MANCINI, L., M.J. PAUL-CLARK, G. ROSIGNOLI, et al. 2007. Calcitonin and pred-nisolone display antagonistic actions on bone and have synergistic effects in ex-perimental arthritis. Am. J. Pathol. 170: 1018–1027.