sanofi-aventis Group has seized an early stage opportunity that opened up when Biogen Idec Inc. recently refocused on neurology, by picking up an obesity and type 2 diabetes program centered on osteocalcin that was previously held by a Biogen incubator company. sanofi is funding external research to identify a receptor responsible for the hormone's metabolic effects and is internally devising strategies to develop osteocalcin or osteocalcin agonists as therapeutics.

In 2007, a team at Columbia University made the surprising discovery that the bone-derived hormone osteocalcin regulates glucose homeostasis in mice.1 The researchers showed that animals treated with osteocalcin had lower blood glucose levels and greater insulin sensitivity than controls,2 which suggested that osteocalcin or osteocalcin agonists could be used to treat patients with metabolic syndrome.

Columbia spun out Escoublac Inc. that year to commercialize the work as the first member of Biogen Idec's Innovation Incubator in Cambridge, Mass.3 However, the fledgling company was shuttered in the fall of 2010 after Biogen announced it would restructure to focus on neurology.4

Biogen spokesperson Naomi Aoki said all of Escoublac's rights
were returned to Columbia because the program was "no longer a strategic fit."

Now, sanofi has entered into a three-year research collaboration with Columbia to investigate the use of osteocalcin as a therapeutic for diabetes management.

"What is really exciting here is that it is a kind of biology that is off the beaten track and not obvious-that is what we are interested in," said Shiv Krishnan, senior director of partnering and innovation at sanofi. "It has a sound physiological basis and is highly translatable in terms of therapeutic concept."

The sponsored research agreement focuses on characterizing the biology and function of osteocalcin. The company has an option to license any findings related to osteocalcin from the lab of Gerard Karsenty.

In house, sanofi is devising plans to develop osteocalcin or a peptide derivative as a therapeutic. That could include screens for small molecule agonists of the osteocalcin pathway as it is further characterized.

According to Krishnan, by the end of the three-year collaboration the company hopes to have a preclinical candidate that could be selected for further development.

Financial details were undisclosed.

Karsenty is professor and chair of genetics and development at Columbia University Medical Center. He led the team that originally discovered a metabolic role for osteocalcin, and he told SciBX that the majority of his lab is focused on answering questions related to osteocalcin biology, including identifying osteocalcin receptors involved in metabolic functions, which could enable the development of small molecule activators of the pathway.

Earlier this year Karsenty's lab published the identification of a receptor for osteocalcin: G protein-coupled receptor family C group 6 member A (GPRC6A).5 However, this receptor has not yet been shown to regulate metabolism and instead plays a role in regulating male fertility-yet another surprising endocrine function for osteocalcin.

Boning up

Escoublac was not idle during its brief life. Karsenty, who also served as chairman of the company's scientific advisory board, said substantial progress had been made over the past three years in understanding how osteocalcin regulates metabolism.

The company performed "exquisite preclinical work on the biochemistry and pharmacology of the hormone," which has advanced the understanding of its pharmacokinetics, Karsenty said.

In addition to Escoublac's work, multiple academic labs have contributed new insights into osteocalcin function. Chief among them was the demonstration that osteocalcin levels are positively correlated with insulin sensitivity in patients with metabolic syndrome or type 2 diabetes, thus lending support for the pathway's relevance in humans.6-8

Additionally, two papers published last year in Cell showed that insulin signals through osteoblasts to regulate levels of osteocalcin.9,10 Thus, osteocalcin and insulin regulate each other in a feedback loop, providing further evidence that the skeletal system is functionally connected to glucose metabolism.

Cain, C. SciBX 4(15); doi:10.1038/scibx.2011.417
Published online April 14, 2011


1.   Lee, N.K. et al. Cell 130, 456-469 (2007)

2.   Ferron, M. et al. Proc. Natl. Acad. Sci. USA 105, 5266-5270 (2008)

3.   Rittenhouse, P. BioCentury 15(55), A10; Dec. 24, 2007

4.   Lawrence, S. BioCentury 18(49) A12-A13; Nov. 8, 2010
5.   Oury, F. et al. Cell 144, 796-809 (2011)

6.   Saleem, U. et al. Arterioscler. Thromb. Vasc. Biol. 30, 1474-1478 (2010)

7.   Yeap, B.B. et al. Eur. J. Endocrinol. 163, 265-272 (2010)

8.   Kanazawa, I. et al. Bone 48, 720-725 (2011)

9.   Fulzele, K. et al. Cell 142, 309-319 (2010)

10. Ferron, M. et al. Cell 142, 296-308 (2010)


      Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.

      Columbia University, New York, N.Y.

      sanofi-aventis Group (Euronext:SAN; NYSE:SNY), Paris, France