The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism
Bone remodelling, which maintains bone mass constant during adulthood, is an energy-demanding process. This, together with the observation that the adipocyte-derived hormone leptin is a major inhibitor of bone remodelling, led to the hypothesis that bone cells regulate energy metabolism through an endocrine mechanism. Studies to test this hypothesis identified osteocalcin, a hormone secreted by osteoblasts, as a positive regulator of insulin secretion, insulin resistance and energy expenditure. Remarkably, insulin signalling in osteoblasts is a positive regulator of osteocalcin production and activation via its ability to indirectly enhance bone resorption by osteoclasts. In contrast, leptin is a potent inhibitor of osteocalcin function through its effect on the sympathetic tone. Hence, osteocalcin is part of a complex signalling network between bone and the organs more classically associated with the regulation of energy homeostasis, such as the pancreas and adipose tissue. This review summarises the molecular and cellular bases of the present knowledge on osteocalcin biology and discusses the potential relevance of osteocalcin to human metabolism and pathology.
KeywordsBone Diabetes Glucose homeostasis Insulin Insulin receptor Leptin Osteoblasts Osteocalcin Osteoclasts Review
HOMA of beta cell function
HOMA of insulin resistance
Biological processes in all cells and organs require energy; bone and the specific cell types overseeing its growth and homeostasis show no exception to this rule. In fact, bone is a particularly energy-expensive organ because it constantly destroys and regenerates itself through a process termed bone remodelling. To fulfil this function, bone hosts two functionally antagonistic cell populations: osteoclasts, which resorb mineralised bone extracellular matrix; and osteoblasts, which deposit new matrix that eventually becomes mineralised. This succession of destruction and formation occurs constantly throughout the skeleton, requiring a constant supply of energy to both cell populations.
Given that the skeleton is one of the largest organs in mammals, one can easily appreciate how the bone remodelling process is metabolically expensive for the body. This observation raises an important physiological question: Is bone remodelling worth its high energetic cost? Looking at the sedentary lifestyle of 21st century man, bone remodelling does not appear to be an essential function. If anything, it is a problem-causing process, since its dysregulation causes one of the most frequent degenerative diseases of the Western hemisphere, osteoporosis. However, if one considers the larger scope of vertebrate evolution, bone remodelling gains considerable credit. By maintaining bone integrity, in particular by preventing microfractures caused by mechanical strains, bone remodelling is key to preserving mobility. In ancient times, mobility meant being able to feed, fight and flee dangers…in other words, survive. From this broader perspective, the energy cost of bone remodelling becomes justifiable since it contributes to the survival of the species. The high cost associated with bone remodelling then raises the possibility that bone cells may have a means of regulating the flow of energy supply/energy storage to fulfil their metabolic needs. Furthermore, when energy is scarce one can logically conceive that there should be mechanisms to restrict bone growth. Studies designed to test these hypotheses have led to the identification of osteocalcin, a novel hormone secreted and activated by bone cells, which is at the core of the cross-talk between bone remodelling and glucose metabolism.
Osteoblasts secrete osteocalcin, a hormone regulating glucose homeostasis
Osteocalcin is activated via its decarboxylation
The decarboxylation of osteocalcin is dependent on bone resorption
Osteocalcin is produced by osteoblasts in a fully carboxylated form, implying that osteocalcin needs to be decarboxylated to become active [5, 6]. However, there is no known extracellular or circulating γ-decarboxylase, suggesting that this process occurs through another mechanism. The elucidation of how ESP activity in osteoblasts is able to inhibit osteocalcin decarboxylation revealed this mechanism.
In addition to their metabolic abnormalities, the Esp-deficient mice also show an increase in bone resorption . Co-culture assays determined that this is due to overactivity of the osteoclasts, which is prompted by the decreased secretion of osteoprotegerin (OPG)—a major inhibitor of osteoclast function—by Esp-deficient osteoblasts . The significance of these findings for osteocalcin biology derives from two observations originally made at least two decades ago. The first is that carboxylated osteocalcin bound to the mineralised bone matrix via its Gla residues can be released upon resorption of this matrix by osteoclasts [11, 12, 13, 14]. The second observation is that Gla residues can be decarboxylated when exposed to acid pH , and that bone resorption precisely involves acidification of the bone matrix. Accordingly, fully carboxylated osteocalcin incubated at a pH of 4.5, the acidity generated at the bone surface by osteoclasts during bone resorption , becomes sufficiently undercarboxylated to induce gene expression in beta cells . Furthermore, media conditioned by osteoclasts that have been seeded onto devitalised bone matrix can stimulate insulin gene expression in beta cells, similar to recombinant osteocalcin . These two in vitro observations suggested that bone resorption is simultaneously responsible for osteocalcin activation and for its release from the mineralised bone matrix, and this was confirmed in vivo using multiple mouse models in addition to pharmacological assays .
Osteocalcin function is regulated by insulin and leptin
Clinical relevance of the osteocalcin-mediated regulation of energy metabolism
That the role of osteocalcin in glucose metabolism and its modes of regulation were uncovered using mouse models raised concerns that this endocrine system could be different or even non-existent in humans. A fast growing number of studies, however, have now established that multiple aspects of osteocalcin biology are similar in rodents and humans. Indeed, levels of circulating osteocalcin have been inversely correlated with BMI, fat mass and plasma glucose levels in adult or elderly men and women of diverse ethnicities [26, 27, 28, 29]. Additional studies have linked low osteocalcin to impaired levels of HbA1c, fasting insulin and insulin resistance (estimated by the HOMA of insulin resistance HOMA-IR) in adult men and women, irrespective of whether they have diabetes [28, 30, 31, 32, 33]. In contrast, serum osteocalcin has been positively correlated with the HOMA of beta cell function (HOMA-%B) in diabetic patients, before and after glycaemic control [33, 34]. Interestingly, plasma levels of osteocalcin are higher in women with gestational diabetes and positively correlate with the disposition index during pregnancy, but return to normal postpartum . This observation suggests that raising serum osteocalcin levels could be part of the adaptive process initiated to counter glucose intolerance during gestational diabetes .
Levels of circulating osteocalcin have also been associated with a number of lipid abnormalities. For instance, serum osteocalcin levels are inversely correlated with levels of adipocyte-specific fatty acid-binding protein (A-FABP) in a mixed population, and with levels of HDL-cholesterol in men, and are positively correlated with total adiponectin levels in post-menopausal women [27, 31, 34]. In addition, an association of decreased levels of osteocalcin with premature myocardial infarction in young patients or with coronary heart disease in older individuals have been reported [34, 36].
More generally, obese individuals have been shown to have lower osteocalcin levels than non-obese controls, and type 2 diabetic individuals have lower plasma osteocalcin than non-diabetic individuals [26, 27, 37]. Higher levels of osteocalcin were also associated with a lower odds ratio of developing metabolic syndrome in black and in white non-Hispanic individuals [29, 38]. A case–control study actually identified coding variants in the fourth exon of human OCN that appeared to correlate with type 2 diabetes in African-American patients . However, this finding should be interpreted cautiously as recent genome-wide association studies of large populations, including one specifically performed on an African-American cohort, did not report an association between variants in the human OCN gene and fasting blood glucose or other traits of diabetes [40, 41].
More recently, studies have begun to assess whether ucOC might be the active form of this hormone in human metabolism, as it is in mice. It has long been known that multiple proteolytic products and undercarboxylated forms of osteocalcin are present in human serum [42, 43]. However, the lack of homogeneity and established specificity of commercially available assays used to detect ucOC considerably limit the study of ucOC [43, 44, 45, 46]. Yet, it was recently shown that ucOC levels are correlated with several metabolic variables. Indeed, higher levels of ucOC are associated with higher insulin secretion, as measured by HOMA-%B, and higher levels of high-molecular-weight adiponectin in healthy children, while lower concentrations of ucOC are associated with impaired fasting glucose and impaired glucose tolerance in children [47, 48]. It has also been reported that, in adult men, serum ucOC is associated with enhanced beta cell function and negatively correlated with fat mass, fasting plasma glucose and HbA1c [30, 49]. Two additional observations support a metabolic role for ucOC in humans by showing that the mechanisms controlling osteocalcin decarboxylation are conserved between humans and rodents. First, although there is no functional Esp gene in humans, the role of ESP in controlling OPG expression is fulfilled in human osteoblasts by another phosphatase, PTP1B (Fig. 2) . Second, patients with impaired bone resorption, the mechanism responsible for osteocalcin decarboxylation in mice, display a decrease in postprandial insulin serum levels .
Therapeutic potential of osteocalcin in the treatment of type 2 diabetes
Mouse genetic data have established osteocalcin as a positive regulator of insulin production and insulin sensitivity. There is also a significant body of clinical correlations between low levels of osteocalcin and various measures associated with diabetes. These combined data suggest that raising serum osteocalcin levels could be a novel therapeutic avenue to prevent or treat diabetes.
The identification of osteocalcin as a novel hormone regulating glucose metabolism and the notion that bone is an endocrine organ opens the door to a new field of investigation. Indeed, not only does the biology of this new hormone need to be explored further, but the existence of additional interactions between bone, pancreas and most likely other organs also need to be identified. From this perspective, the identification of the osteocalcin receptor will likely be a pivotal step.
Additional studies are also necessary to evaluate the impact of the bone metabolism connection in humans. For example, it was recently shown that postmenopausal osteoporotic women treated with alendronate, which inhibits bone resorption, have lower levels of osteocalcin . It would therefore be important to test whether anti-resorptive treatments, which are the main therapeutic approach to osteoporosis at the present time, might in some cases have a negative effect on glucose tolerance. Likewise, anticoagulating agents that affect the function of vitamin K, and therefore the γ-carboxylation of osteocalcin , could potentially have an unrecognised effect on glucose metabolism. The view that osteocalcin is only a marker of bone formation should also be revisited since, at least in some cases, variations in its serum levels might reflect a transient metabolic adaptation rather than a primary effect on bone formation. In line with this notion, there was a negative association of osteocalcin levels with impaired fasting glucose and impaired glucose tolerance in overweight children but not with bone mineral content . More generally, analysis of the effects of some glucose-lowering agents on the production or activation of osteocalcin may provide novel insights on their mechanism of action.
Duality of interest
The author declares that there is no duality of interest associated with this manuscript.