Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms

Osteoporosis, a global age-related health problem in both male and female elderly, insidiously deteriorates the microstructure of bone, particularly at trabecular sites, such as vertebrae, ribs and hips, culminating in fragility fractures, pain and disability. Although osteoporosis is normally associated with senescence and estrogen deficiency, diabetes mellitus (DM), especially type 1 DM, also contributes to and/or aggravates bone loss in osteoporotic patients. This topic highlight article focuses on DM-induced osteoporosis and DM/osteoporosis comorbidity, covering alterations in bone metabolism as well as factors regulating bone growth under diabetic conditions including, insulin, insulin-like growth factor-1 and angiogenesis. Cellular and molecular mechanisms of DM-related bone loss are also discussed. This information provides a foundation for the better understanding of diabetic complications and for development of early screening and prevention of osteoporosis in diabetic patients

Enhanced trabecular bone resorption and microstructural bone changes in rats after removal of the cecum

Item does not contain fulltextThe cecum, the proximal part of the large intestine, has the highest rate of calcium absorption compared with other intestinal segments. Previously, we showed that rats with the cecum surgically removed (cecectomized rats) had severe negative calcium balance, low bone mineral density (BMD), and a compensatory increase in colonic calcium absorption. Herein, we used the computer-assisted bone histomorphometric technique and microcomputed tomography (muCT) to analyze bone microstructural defects in cecectomized rats at 1 and 3 mo postsurgery compared with age-matched sham-operated control rats. Relatively low BMD as determined by dual energy X-ray absorptiometry was observed in the femora, tibiae, and lumbar vertebrae of the 3-mo cecectomized rats. muCT analysis revealed decreases in the tibial cortical thickness, periosteal and endosteal perimeters, and moment of inertia in cecectomized rats. The histomorphometric results further showed that trabecular bone volume and number were markedly decreased, whereas trabecular separation was increased in the proximal tibial metaphysis of cecectomized rats, thus leading to a decrease in trabecular volumetric BMD. Since osteoclast surface and eroded surface were increased after cecectomy, such bone loss in cecectomized rats appeared to result from an enhanced bone resorption. Moreover, decreases in bone formation rate and osteoblast surface indicated a suppression of osteoblast-mediated bone formation. In conclusion, cecectomy induced widespread osteopenia in rats presumably by enhancing the osteoclast-mediated bone resorption and suppressing bone formation. The present results underline the important role of cecum in the body calcium homeostasis

Impaired body calcium metabolism with low bone density and compensatory colonic calcium absorption in cecectomized rats

Item does not contain fulltextAn earlier study reported that cecal calcium absorption contributes less than 10% of total calcium absorbed by the intestine, although the cecum has the highest calcium transport rate compared with other intestinal segments. Thus, the physiological significance of the cecum pertaining to body calcium metabolism remains elusive. Herein, a 4-wk calcium balance study in cecectomized rats revealed an increase in fecal calcium loss with marked decreases in fractional calcium absorption and urinary calcium excretion only in the early days post-operation, suggesting the presence of a compensatory mechanism to minimize intestinal calcium wasting. Further investigation in cecectomized rats showed that active calcium transport was enhanced in the proximal colon but not in the small intestine, whereas passive calcium transport along the whole intestine was unaltered. Since apical exposure to calcium-sensing receptor (CaSR) agonists similarly increased proximal colonic calcium transport, activation of apical CaSR in colonic epithelial cells could have been involved in this hyperabsorption. Calcium transporter genes, i.e., TRPV6 and calbindin-D(9k), were also upregulated in proximal colonic epithelial cells. Surprisingly, elevated serum parathyroid hormone levels and hyperphosphatemia were evident in cecectomized rats despite normal plasma calcium levels, suggesting that colonic compensation alone might be insufficient to maintain normocalcemia. Thus, massive bone loss occurred in both cortical and trabecular sites, including lumbar vertebrae, femora, and tibiae. The presence of compensatory colonic calcium hyperabsorption with pervasive osteopenia in cecectomized rats therefore corroborates that the cecum is extremely crucial for body calcium homeostasis

The role of FeCl₃ on calcium transport across Caco-2 monolayer pre-treated with 1,25(OH)₂D₃ and ascorbic acid (Asc).

(A) Experimental timeline (please see text for detail). (B–E) Transepithelial calcium transport and epithelial electrical parameters (PD, Isc, and TER) in Caco-2 monolayers with or without 10 nM 1,25(OH)2D3, 200 μM FeCl3, and 0.5 mM Asc. PD values were the magnitudes of potential difference (the apical side being negative with respect to the basolateral side), and glucose made the apical side more negative. (n = 10; *P P ††P †††P 2D3-treated group (blue bar).</p

Expression of genes and proteins related to transepithelial calcium transport, and transepithelial resistance in Caco-2 cells.

(A) Expression of TRPV6, calbindin-D9k, PMCA1b and NCX1 mRNA, as determined by quantitative real-time PCR. Representative fluorescent photomicrographs from conventional fluorescent microscope (400×; Nikon model Eclipse Ni-U) and confocal laser scanning microscope (630×; Carl Zeiss model Zeiss LSM800) confirmed the presence of TRPV6 (red) and PMCA1b (green) protein expression in 3-day Caco-2 monolayer [blue, nuclei stained with 4′,6-diamidino-2-phenylindole (DAPI)]. The drawing diagram shows localization of calcium transporters in a Caco-2 cell. TRPV6, transient receptor potential vanilloid subfamily member 6; PMCA1b, plasma membrane Ca2+-ATPase 1b; NCX1, Na+/Ca2+ exchanger 1; NKA, Na+/K+-ATPase. (B) Transepithelial resistance (TER) of Caco-2 cells after being cultured on Snapwells for 3 or 6 days (n = 4/group; two-tailed, unpaired Student’s t-test). NS, not significant.</p

The effects of VIP/pituitary adenylate cyclase-activating polypeptide receptor (VPAC) agonist on intestinal epithelium-like Caco-2 monolayers.

(A) Timeline of Experiment 1. (B) Transepithelial calcium flux and (C–E) epithelial electrical parameters (PD, Isc, and TER) across Caco-2 monolayers that were directly exposed to 0.1 and 1 μM VPAC agonist on the basolateral side for 30 min. *p < 0.05 vs. control group (open bar, one-way ANOVA with Tukey’s multiple comparison test).</p