Physiology Bones Calling Pancreas, Come In Please

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

It has been previously found that fat cells release a hormone that regulates bone remodeling. The concept of homeostasis suggests that bone should be able to signal back to the tissues that regulate metabolism to establish a feedback system. Lee et al. sought such an endocrine connection and screened mice in which genes specifically expressed in osteoblasts (the cells responsible for bone deposition) were knocked out for altered metabolism. Using this approach, they identified the Esp gene, which encodes a protein tyrosine phosphatase called OST-PTP that is present only in osteoblasts and Sertoli cells. (Analysis of knockout mice or mice with targeted disruption of the gene only in osteoblasts showed the same phenotypes, and these are referred to collectively as Esp^–/–.) The Esp^–/– mice showed increased perinatal lethality, increased pancreatic cell mass, increased circulating concentrations of insulin and adiponectin, decreased blood glucose concentration, and increased glucose tolerance. Adiponectin is released by adipocytes and enhances insulin sensitivity. In addition, the Esp^–/– mice were resistant to obesity and glucose intolerance caused by a high-fat diet or excessive food intake (caused by lesioning the ventromedial hypothalamus). The metabolic alterations in the Esp^–/– mice were reversed if the mice were heterozygous for the gene encoding osteocalcin, an osteoblast-secreted protein, suggesting that OST-PTP regulates osteocalcin. However, the concentration of circulating osteocalcin was normal in the Esp^–/– mice; therefore, OST-PTP influences the bioactivity of osteocalcin. Osteocalcin is posttranslationally modified by -carboxylation of glutamic acid residues, and in the Esp^–/– mice the abundance of uncarboxylated osteocalcin relative to carboxylated osteocalcin in circulation was increased. Coculture experiments with wild-type osteoblasts, Esp^–/– osteoblasts, or warfarin-treated osteoblasts (warfarin inhibits -carboxylation) and adipocytes or pancreatic cells supported the hypothesis that uncarboxylated osteocalcin is the bioactive form and that the release of the uncarboxylated form of Esp^–/– osteoblasts is elevated. These results have important clinical implications (see Semenkovich and Teitelbaum). First, they point to additional targets (osteocalcin, OST-PTP, and the enzymes involved in osteocalcin -carboxylation) for treating obesity and diabetes. Second, warfarin is used clinically to treat thrombosis. The effect on metabolism in these patients should be investigated. Third, treatments used for osteoporosis prevention inhibit bone remodeling and may alter this homeostatic mechanism linking the skeleton to energy metabolism. Finally, this may provide a mechanistic framework for understanding the effects of glucocorticoid treatment on metabolism and bone remodeling as dependent and not independent effects.

N. K. Lee, H. Sowa, E. Hinoi, M. Ferron, J. D. Ahn, C. Confavreux, R. Dacquin, P. J. Mee, M. D. McKee, D. Y. Jung, Z. Zhang, J. K. Kim, F. Mauvais-Jarvis, P. Ducy, G. Karsenty, Endocrine regulation of energy metabolism by the skeleton. Cell 130, 456-469 (2007). [Online Journal]

C. F. Semenkovich, S. L. Teitelbaum, Bone weighs in on obesity. Cell 130, 409-411 (2007). [Online Journal]

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