Osteocalcin: An Endocrine Link Between Bone and Glucose Metabolism

Bu B Yeap

Disclosures

Expert Rev Endocrinol Metab. 2011;6(2):177-185. 

In This Article

Bone is an Endocrine Organ that Regulates Glucose Metabolism in Mice

Obesity, impaired fasting glucose and impaired glucose tolerance are associated with an increased risk of developing Type 2 diabetes.[15] Type 2 diabetes arises from insulin resistance in body tissues (e.g., in liver, muscle and fat) and progressive impairment of pancreatic β-cell insulin secretion.[16] Recent studies in knockout mice have identified a novel mechanism by which cells involved in bone formation (osteoblasts) regulate glucose metabolism, modulating both β-cell insulin secretion and peripheral insulin resistance.[17] In these studies, enterococcal surface protein (Esp)-knockout mice (Esp−/−) lacking an osteoblast-expressed receptor-like protein tyrosine phosphatase (OST-PTP) displayed increased β-cell proliferation, hyperinsulinemia, lower glucose levels, and were protected from developing diabetes. Compared with wild-type mice, Esp−/− mice exhibited increased insulin sensitivity, increased expression of adiponectin in fat tissue and a twofold increase in serum adiponectin (Figure 1A).[17] In mice, OST-PTP is expressed in bone and testis and not in the pancreas, and mice with osteoblast-specific deletion of OST-PTP possessed the same diabetes-resistant phenotype as Esp−/− mice, suggesting mediation by an endocrine or humoral factor. In humans, there are >30 tyrosine phosphatases, one of which might possibly mediate this pathway, but the closest human homolog of OST-PTP is a pseudogene and thus not a viable target for new antidiabetic drugs.[18] However, the diabetes-resistant Esp−/− phenotype was completely reversed by deletion of a single allele of osteocalcin (Ocn), implicating this distinct osteoblast-secreted circulating protein as a novel bone-derived endocrine regulator of glucose homeostasis (Figure 1B).[17]

Figure 1.

Osteoblast-secreted osteocalcin is a novel bone-derived endocrine regulator of glucose homeostasis in mice.
(A) Knockout mice (Esp −/−) lacking an osteoblast-expressed receptor-like protein tyrosine phosphatase are protected from diabetes.
(B) This phenotype is neutralized by the deletion of a single allelle of osteocalcin and (C) Ocn −/− mice are glucose intolerant. Esp: Enterococcal surface protein; Ocn: Osteocalcin.

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