Trends in Endocrinology & Metabolism
ReviewBone as an endocrine organ
Section snippets
Much more to bone than you might have thought
Until recently, endocrinologists have looked upon bone as a target for hormones such as sex steroids, parathyroid hormone (PTH) and calcitonin. Immunologists and hematologists classically viewed the skeleton as a mere protective casing for cells and their cytokine products, and neurobiologists perhaps only thought of bone as a useful support system. Discoveries in the past few years have changed this, making us realize from an evolutionary point of view how important the skeleton is for
The bone-derived hormone FGF23
The discovery of FGF23 revealed a tightly controlled system regulating serum phosphate and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels, produced in bone and acting on the kidney through a specific receptor (Figure 1). This newly discovered regulation of serum phosphate by FGF23 is independent of PTH or the vitamin D endocrine system 3, 4, which are already known to affect serum phosphate levels. Furthermore, FGF23 excess or deficiency resulted in several abnormalities of phosphate metabolism.
FGF23 action
When Chinese hamster ovary cells stably expressing FGF23 were implanted into athymic nude mice, the animals developed hypophosphatemia, impaired renal tubular phosphate reabsorption, low 1,25(OH)2D levels and rachitic changes in bone, thus mimicking the biochemical and clinical features of TIO and ADHR [7]. The same changes in phosphate and 1,25(OH)2D resulted from injection of recombinant FGF23 into mice [3], with further experiments delineating the relevant pathways regulated by FGF23 in
Sites of FGF23 production and receptor interactions
Although FGF23 seemed to be predominantly expressed in the ventrolateral thalamic nucleus in mice [5], weak FGF23 expression was also observed in liver, heart, thymus and lymph node [7]. Attractive though the idea was that FGF23 is a hormone, it was essential to identify the site of the ‘gland’. Several studies pointed to bone as a primary site of FGF23 production. First, knock-in of the LacZ gene into the FGF23 locus indicated that FGF23 is predominantly expressed in bone after birth [12].
Diseases caused by aberrant FGF23 actions
Many diseases have been found to be caused by aberrant actions of FGF23 (Table 1). An in vitro study indicated that FGF23 protein can be cleaved into inactive fragments between Arg179 and Ser180 by subtilisin-like proteases [29]. Mutant FGF23 proteins in patients with ADHR were shown to be resistant to this processing 30, 31. In addition to this resistance, the regulatory mechanism of FGF23 production seems to be deranged in these patients because circulatory FGF23 is sometimes, but not always,
Osteocalcin, a bone hormone controlling energy metabolism
Even greater surprises came from the discovery of the osteoblast-specific protein osteocalcin. Loss- and gain-of-function studies and pharmacological experiments in mice have shown osteocalcin to be a hormone that increases insulin production and sensitivity, enhancing glucose utilization and energy expenditure [54]. These findings have been reviewed recently in TEM[55].
Osteocalcin (also called bone γ-carboxyglutamic acid protein, or BGP), is a bone-specific protein of 46–50 residues that
Clinical diabetes and osteocalcin
The implications of these discoveries for type II diabetes and the metabolic syndrome are many, as are those for physiology in general. There are few recent clinical studies, and further information will evoke much interest. In two cross-sectional studies, blood osteocalcin levels were significantly lower in diabetics than in non-diabetic controls and levels were inversely related to fat mass and blood glucose 62, 63. In postmenopausal women, osteocalcin levels were significantly lower in type
Concluding remarks
The concept of the skeleton as a ductless gland, responding to environmental influences of metabolism and energy requirements by producing a hormone with such actions, is a revolutionary one. It helps us realize the importance of the skeleton in mammalian survival, confirmed by the remarkable number of dramatic bone phenotypes emerging as the result of genetic manipulation of mice. It makes evolutionary sense that bone produces a hormone that regulates the metabolism of phosphate, cooperating
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