The prevailing paradigm in skeletal biology is that differentiation and functions of the two bone-specific cell types, osteoblasts and osteoclasts, are determined by secreted molecules that can either be cytokines acting locally, or hormones acting systemically (Harada and Rodan, 2003
; Teitelbaum and Ross, 2003
). A remarkable feature of most hormonal regulations is that they are controlled by feedback loops such that a cell type affected by a hormone sends signals influencing the hormone-producing cell. When applied to skeletal biology the concept of feedback regulation suggests that bone cells may exert an endocrine function.
Bone remodeling, the process whereby bones renew themselves, is regulated by multiple hormones. That obesity protects mammals from osteoporosis led us to propose that bone remodeling and energy metabolism could be regulated by the same hormone(s) (Ducy et al., 2000a
). Verifying this hypothesis we showed that leptin, an adipocyte-derived hormone that appears during evolution with bony skeleton, is a major regulator of bone remodeling by acting on osteoblasts through two different neural pathways (Karsenty, 2006
). Regardless of the molecular complexity of this novel neuroendocrine regulation, if indeed bone cells determine the level of activity of hormone-producing cells, then osteoblasts should affect energy metabolism.
Osteocalcin, one of the very few osteoblast-specific proteins, has several features of a hormone. It is, for instance, a cell-specific molecule, synthesized as a pre-pro-molecule and secreted in the general circulation (Hauschka et al., 1989
; Price, 1989
). Because of their exquisite cell-specific expression the Osteocalcin
genes have been intensively studied to identify osteoblast-specific transcription factors and to define molecular bases of bone physiology (Harada and Rodan, 2003
). In the course of the latter study we generated Osteocalcin
−/ − mice (Ducy et al., 1996
). While analyzing these mutant mice we noticed that they had an abnormal amount of visceral fat (P. D. and G. K., unpublished observation). This was the first evidence suggesting that skeleton may regulate energy metabolism.
Osteocalcin undergoes an unusual post-translational modification whereby glutamic acid residues are carboxylated to form γ-carboxyglutamic acid (Gla) residues, hence its other name, bone Gla protein (Hauschka et al., 1989
). Gla residues usually confer to proteins high affinity for mineral ions, yet loss- and gain-of function experiments have failed to identify a function for osteocalcin in extracellular matrix mineralization in vivo (Ducy et al., 1996
; Murshed et al., 2004
). Thus at the present time the biological role, if any, of osteocalcin γ-carboxylation remains unknown.
A characteristic of osteoblasts is their paucity of cell-specific gene expression. We took advantage of this property and, with the goal of identifying osteoblast-enriched genes affecting energy metabolism, generated mutant mouse strains lacking genes encoding signaling molecules expressed only or preferentially in osteoblasts. Through this effort we inactivated, via classical means and in an osteoblast-specific manner, Esp
also known as Ptprv
, a gene expressed in osteoblasts and Sertoli cells that encodes a receptor-like protein tyrosine phosphatase termed OST-PTP (Mauro et al., 1994
). Remarkably, mice lacking Esp
in osteoblasts only display an increase in β-cell proliferation, insulin secretion and sensitivity that protects them from induced obesity and diabetes; all these phenotypes are corrected by deleting one allele of Osteocalcin.
Accordingly, Osteocalcin−/ −
mice are glucose intolerant and fat; genetic and cell-based assays show that osteocalcin can favor proliferation of pancreatic β-cells, Insulin
expression in β-cells and adipocytes. To our knowledge this study provides the first in vivo evidence that skeleton exerts an endocrine regulation of energy metabolism and thereby may contribute to the onset and severity of metabolic disorders.