Regulation of osteocalcin secretion and its therapeutic implication

Columbia University Health Sciences, New York NY

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Abstract

Project Summary- Project #1- Lead PI- Karsenty Since its purification in the late 70s, osteocalcin has traditionally been viewed as a structural component of the bone extracellular matrix (ECM) that might possibly be implicated in bone mineralization. The emergence of genetics in model organisms has allowed us and other to study the function of this protein in vivo and in the entire animal. This investigation, which was conducted nearly 30 years ago in one mouse of osteocalcin deficiency and reproduced in the last year in two other mouse strains of osteocalcin deficiency, allowed us to make three types of conclusions. The first one is that bone mineralization is not affected to a level that becomes clinically relevant in the absence of osteocalcin in the mouse. A second one that is the topic of this application and was also observed in rats lacking Osteocalcin is that osteocalcin is an inhibitor of bone mass accrual. This phenotype has never been explained since its initial description in 1996. A third observation again established in three mouse models of osteocalcin deficiency is that regardless of sex, genetic background, age, mode of generation, and analysis of mice, osteocalcin is a hormone with a remarkably broad reach. Two characteristics of osteocalcin as a hormone led us to revisit the high bone mass phenotype of Osteocalcin-/- mice. The first one is that for most functions it regulates osteocalcin acts as a regulator of other hormones or neurotransmitters. That actually perform the function under study. A second characteristic is that osteocalcin signaling in the brain regulates the production of brain-derived serotonin. Since serotonin does not cross the blood-brain barrier, this latter observation raises the prospect that osteocalcin might also regulate the synthesis of gut-derived serotonin, which is initiated by Tryptophane hydroxylase 1, an enzyme present in enterochromaffin cells of the gut but not in neurons of the brainstem where serotonin is also synthesized. This observation becomes relevant to this project because gut-derived serotonin is an inhibitor of bone mass accrual. Testing this hypothesis revealed that osteocalcin indeed regulates gut-derived serotonin production and circulating serotonin levels, thus revealing the existence of a reciprocal cross-talk between bone and the gastrointestinal tract that may regulate bone mass accrual. To test this hypothesis, we enlisted the help of a world expert in intestinal epithelium physiology (Dr. Kelley Yan). We gathered all the genetic and molecular tools needed to test our working hypothesis. Our Specific Aims are:  To demonstrate in consultation with Project 2 and the help of core B that osteocalcin regulates bone mass by regulating gut-derived serotonin synthesis before and/or after birth.  To identify and study the function of the receptor of osteocalcin expressed in enterochromaffin cells and that mediate its regulation of the synthesis of gut-derived serotonin.  determine with the help of Core C the mechanisms used by osteocalcin signaling to regulate serotonin production by the gut epithelium.