Possible involvement of HtrA1 serine protease in the onset of osteoporotic bone extracellular matrix changes.

High-temperature requirement A1 (HtrA1), a multidomain serine protease acting on Extracellular matrix (ECM) rearrangement, is also secreted by osteoblasts and osteoclasts. Recent and conflicting literature highlights HtrA1's role as a controller of bone remodeling, proposing it as a possible target for pathologies with unbalanced bone resorption, like Osteoporosis (OP). To add knowledge on this molecule function in bone physiopathology, here we compared HtrA1 distribution in the ECM of healthy (H) and OP bone tissue, also examining its localization in the sites of new bone formation. HtrA1 was homogeneously expressed in the mature bone ECM of H tissue showing a 55.6 ± 16.4% of the stained area, with a significant (p=0.0001) decrease in OP percentage stained area (21.1 ± 13.1). Moreover, HtrA1 was present in the endosteum and cells involved in osteogenesis, mainly in those "entrapped" in woven bone, whereas osteocytes in mature lamellar bone were negative. Based on our previous observation in OP tissue of a significantly increased expression of Decorin and Osteocalcin, both involved in bone mineralization and remodeling and equally substrates for HtrA1, we speculate that HtrA1 by controlling the proper amount of Decorin and Osteocalcin favors normal bone maturation and mineralization. Besides, we suggest that late-osteoblasts and pre-osteocytes secrete HtrA1 in the adjacent matrix whilst proceeding with their maturation and that HtrA1 expression is further modified during the remodeling from woven to the lamellar bone. Overall, our data suggest HtrA1 as a positive regulator of bone matrix formation and maturation: its reduced expression in mature OP bone, affecting protein content and distribution, could hamper correct bone remodeling and mineralization.

In vivo relationship between insulin and endothelin role of insulin-resistance.

Since endothelin production is stimulated in vitro by insulin, we performed this study to evaluate in vivo the relationships between endothelin and insulin plasma levels during a glucose load. We studied 28 subjects; 17 with normal glucose tolerance (NGT) and 11 with impaired glucose tolerance (IGT). Ten of the subjects in this study were normotensive and 18 with mild to moderate hypertension. Age, sex and body mass index were comparable among the groups. After a 2-week period of washout they underwent an oral glucose tolerance test; blood was drawn at 0 (basal), 90 and 120 min after the load for determination of glucose, insulin, C-peptide of insulin and endothelin-1 and -2. Basal endothelin in all the subjects under study was correlated with basal insulin; moreover it was negatively related with the glucose:insulin ratio that has been considered as an insulin-sensitivity index and positively with the insulin:C-peptide ratio as hepatic insulin-resistance index. The relationship between basal endothelin and insulin values was also found in each glucose tolerance group. At 120 min after the glucose load, mean plasma values of endothelin were significantly higher (6.66 +/- 1.31 vs 4.17 +/- 0.61 pmol/L); moreover, the per cent increase of endothelin at 120 min was positively related to the per cent increase of insulin. Between the normotensive and hypertensive groups there were no significant differences in studied endothelin parameters. Our results appear to confirm that, even in vivo, insulin modulates circulating endothelin levels.

Insulin-like growth factor 1 and pressure load in hypertensive patients.

To verify the effect of a pressure load on the production of Insulin-like Growth Factor 1 (IGF1) in essential hypertensives, we studied 15 patients and 8 normotensive controls before and during orthostatism. Upright standing was characterized both in normals and in hypertensives by significant higher rate-pressure product [RPP = systolic blood pressure (mm Hg) x heart rate (beats/min)]. Proportional increases of RPP were significantly related to IGF1 values at the end of orthostatism and to proportional increases of IGF1 in hypertensive group but not in normotensive one. Our results confirm that IGF1 plasma levels in hypertensive patients are related to pressure load.