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The Endogenous Growth Hormone Secretagogue (Ghrelin) Is Synthesized and Secreted by Chondrocytes

Departments of Physiology (J.E.C., C.D.), Morphological Sciences (T.G.-C., M.B., R.G.), and Medicine, Molecular Endocrinology Section (F.F.C.), University of Santiago de Compostela; and Complexo Hospitalario Universitario de Santiago (O.G., M.O., J.J.G.-R.), Research Area, Laboratory 4, NEIRID Lab (NeuroEndocrine Interactions in Rheumatology and Inflammatory Diseases), and Complexo Hospitalario Universitario de Santiago (F.L.), Research Area, Laboratory 1, Molecular and Cellular Cardiology Unit, Santiago de Compostela 15706, Spain; and Beth Israel Deaconess Medical Center (M.B.G.), Division of Rheumatology, New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, Massachusetts 02115-5713

Address all correspondence and requests for reprints to: Oreste Gualillo, Ph.D., Santiago University Clinical Hospital, Research Area, Research Laboratory 4, Trav. Choupana, sn, 15706 Santiago de Compostela, Spain. E-mail: gualillo{at}usc.es.

Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHS-R), is a recently isolated hormone, prevalently expressed in stomach but also in other tissues such as hypothalamus and placenta. This novel acylated peptide acts at a central level to stimulate GH secretion and, notably, to regulate food intake. However, the existence of further, as yet unknown, effects or presence of ghrelin in peripheral tissues cannot be ruled out. In this report, we provide clear evidence for the expression of ghrelin peptide and mRNA in human, mouse, and rat chondrocytes. Immunoreactive ghrelin was identified by immunohistochemistry in rat cartilage, being localized prevalently in proliferative and maturative zone of the epiphyseal growth plate, and in mouse and human chondrocytic cell lines. Moreover, ghrelin mRNA was detected by RT-PCR and confirmed by Southern analysis in rat cartilage as well as in mouse and human chondrocytes cell lines. Ghrelin mRNA expression has been studied in rat along early life development showing a stable profile of expression throughout. Although ghrelin expression in chondrocytes suggests the presence of an unexpected autocrine/paracrine pathway, we failed to identify the functional GH secretagogue receptor type 1A by RT-PCR. On the other hand, binding analysis with ¹²⁵I ghrelin suggests the presence of specific receptors different from the 1A isotype. Scatchard analysis revealed the presence of two receptors with respectively high and low affinity. Finally, ghrelin, in vitro, was able to significantly stimulate cAMP production and inhibits chondrocytes metabolic activity both in human and murine chondrocytes. In addition, ghrelin is able to actively decrease both spontaneous or insulin-induced long chain fatty acid uptake in human and mouse chondrocytes. This study is the first to provide evidence for the presence of this novel peptide in chondrocytes and suggests novel potential roles for this newly recognized component of the GH axis in cartilage metabolism.

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