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Osteocalcin promotes bone mineralization but is not a hormone

2020; Public Library of Science; Volume: 16; Issue: 6 Linguagem: Inglês

10.1371/journal.pgen.1008714

1553-7404

Stavros C. Manolagas,

Bone Metabolism and Diseases

During the last 24 years the bone and mineral metabolism research community (and the National Institutes of Health and numerous other national and international funding agencies that support it) have devoted a great deal of intellectual energy and resources to some provocative, sometimes controversial, ideas about osteocalcin (OCN).OCN is a 46 amino-acid protein that is produced and secreted almost exclusively by osteoblasts, terminally differentiated cells responsible for the synthesis and mineralization of bone matrix during development of the skeleton and its periodic regeneration throughout life.Osteoblasts originate from mesenchymal progenitors and are short-lived cells that are constantly replaced, depending on the demand for bone formation in a particular location and time [1].OCN secreted by osteoblasts contains three γ-carboxyglutamic acid residues that confer high affinity to the bone hydroxyapatite matrix.However, when bone is resorbed by osteoclasts, a macrophage-derived cell type, the acidic pH in the resorption compartment causes the carboxyl groups on OCN to be removed, and decarboxylated OCN is released into circulation.The circulating levels of decarboxylated OCN are, therefore, dependent on the rate of bone turnover, also known as remodeling.Originally thought to function exclusively in bone, a more expansive view of decarboxylated OCN as an endocrine hormone has evolved, largely through work of Gerard Karsenty and colleagues and beginning with the description of an OCN knockout mouse 24 years ago [2].As a hormone, OCN has been proposed to act on multiple end organs and tissues including the pancreas, liver, fat cells, muscle, male gonads, and brain to regulate functions ranging from bone mass accumulation to body weight, adiposity, glucose and energy metabolism, male fertility, brain development, and cognition [2][3][4][5][6].This idea-that OCN is an endocrine hormone with pleiotropic effects-is widely cited in textbooks and review articles [7,8] and has provided the rationale for numerous human studies on the relationship between OCN and diabetes or obesity.There have been, however, several apparent shortcomings in the "OCN is an endocrine hormone" idea.The number of osteoblasts (and therefore the circulating levels of decarboxylated OCN) inexorably change throughout life as a result of physiologic, adaptive, or pathologic changes of bone itself that can be acute or chronic, systemic or localized, and reversible or irreversible, without changes in the putative extraskeletal targets of decarboxylated OCN.Examples are skeletal development, growth, adaptation of the skeleton to mechanical forces, fracture healing, changing calcium needs, stress, menstrual cycle, pregnancy, lactation, menopause, aging, hyperparathyroidism or hypoparathyroidism, hyperthyroidism, hypercortisolemia, Paget's disease, bone tumors, etc.Similarly, medications-approved after extensive trials with