endothelin-1 and Bone-Diseases--Metabolic

Bone is a dynamic tissue that undergoes a precise remodeling process involving resorptive osteoclastic cells and bone-forming osteoblastic (OB) cells. The functional imbalance of either of these cell types can lead to severe skeletal diseases. The proliferation and differentiation of OB cells play a major role in bone development and turnover. These cellular processes are coordinated by connexin43 (Cx43)-based gap-junctional intercellular communication (GJIC) and by soluble factors such as endothelin-1 (ET-1). We have used the Cx43 heterozygous (Cx43(+/-)) murine model to study the possible cross-talk between Cx43 and ET-1 in cultured calvarial OB cells. On microcomputed tomographic analysis of 3-day-old pups, Cx43(+/-) mice showed hypomineralized calvaria in comparison with their Cx43(+/+) littermates. Characterization of cultured OB cells clearly demonstrated the effect of the partial deletion of the Cx43 gene on its expression, on GJIC, and subsequently on OB differentiation. In this model, ET-1 (10(-8) M) lost its mitogenic action in Cx43(+/-) OB cells compared with Cx43(+/+) cells. Moreover, a correlation between the inhibition of cell differentiation by ET-1 and the decreased amount and function of Cx43 was found in Cx43(+/+) OB cells but not in their Cx43(+/-) counterparts. Thus, as Cx43 is linked to OB differentiation, our data indicate that this mitogenic ET-1 peptide has pronounced effects on fully differentiated OB cells. With respect to roles in mechanotransduction and OB differentiation, Cx43 might modulate osteoblastic sensitivity to soluble factors.

Topics: Animals; Bone Diseases, Metabolic; Bone Remodeling; Calcification, Physiologic; Cell Communication; Cell Differentiation; Cell Division; Cell Proliferation; Connexin 43; Endothelin-1; Gap Junctions; Growth Inhibitors; Mechanotransduction, Cellular; Mice; Mice, Knockout; Mice, Transgenic; Organ Culture Techniques; Osteoblasts; Osteogenesis; Skull; X-Ray Microtomography

Low bone mineral density is highly prevalent in postmenopausal women. Osteopenia in postmenopausal women is a predictor of adverse cardiovascular events. A potential mechanism contributing to the increased cardiovascular risk in postmenopausal women with osteopenia is endothelial vasomotor dysfunction. Endothelin (ET)-1 is a potent vasoconstrictor peptide that is associated with endothelial vasomotor dysfunction and increased cardiovascular risk. Currently, there is no information on osteopenia and ET-1 vasoconstrictor activity in postmenopausal women. We tested the hypothesis that ET-1 mediated vasoconstrictor activity is greater in postmenopausal women with osteopenia compared with those without. Forearm blood flow responses to intra-arterial infusion of BQ-123 (100 nmol/min for 60 min), a selective ET(A) receptor antagonist, were determined in postmenopausal women: 10 with osteopenia (age: 56+/-1 yr, lumbar spine T-score between -1.5 and -2.5) and 12 without osteopenia (age: 60+/-2 yr, T-score>-1.5). In women with osteopenia, forearm blood flow increased approximately 25% (P<0.05) in response to BQ-123. However, in the women without osteopenia, resting forearm blood flow was not significantly changed. In conclusion, these results suggest that osteopenia is associated with greater ET-1-mediated vasoconstrictor tone. Increased ET-1 vasoconstrictor activity may contribute to the elevated cardiovascular risk in postmenopausal women with osteopenia.

Topics: Antihypertensive Agents; Bone Density; Bone Diseases, Metabolic; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Humans; Middle Aged; Muscle Tonus; Muscle, Smooth, Vascular; Peptides, Cyclic; Postmenopause; Regional Blood Flow; Vasoconstriction; Vasoconstrictor Agents