Transforming growth factor-beta enhances calcitonin-induced cyclic AMP production and the number of calcitonin receptors in long-term cultures of human umbilical cord blood monocytes in the presence of 1,25-dihydroxycholecalciferol.
ABSTRACT Transforming growth factor-beta (TGF-beta) is a multifunctional polypeptide, abundant in bone, that regulates both proliferation and differentiation of a wide variety of cells, but its role in osteoclast differentiation remains controversial. We have recently shown that long-term cultures of human cord blood monocytes, in the presence of 1,25 dihydroxycholecalciferol (1,25-(OH)2D3), give rise to cells that express two markers of the osteoclast phenotype, namely, the vitronectin receptor (VNR) and the calcitonin receptor (CTR). TGF-beta enhanced the proportion of cells expressing the VNR. In the present study, we investigated the effect of TGF-beta on the expression of CTR in cord blood monocytes cultured during 3 weeks in the presence of 1,25-(OH)2D3. When added within the first 2 weeks of culture, TGF-beta (500 pg/ml) significantly decreased the cell protein content. TGF-beta alone did not stimulate basal cAMP production. The 10 nM-sCT-stimulated cAMP production was enhanced by increasing TGF-beta concentrations from 50 pg/ml to 1,000 pg/ml: for 500 pg/ml TGF-beta, it was 294 +/- 28% vs. 140 +/- 25% for control cultures (p less than 0.01). The sCT dose-response curves showed a higher cAMP production from 10(-9) M to 10(-7) M of sCT in the presence of 500 pg/ml TGF-beta than in control cultures. The increase was 325 +/- 36% in the presence of TGF-beta and 195 +/- 13% in the absence of TGF-beta, for 10(-7) M sCT (p less than 0.01). This effect of TGF-beta on cAMP production was not observed either when it was added to monocyte cultures the last day or 2 hours before the end of the culture or in MCF7, a human breast cancer cell line that expresses CTR. [125I]-sCT binding studies performed on confluent cells showed similar Kd in control and TGF-beta-treated cells. By contrast, the CTR number was significantly increased in the presence of TGF-beta: 6.1 +/- 2 x 10(4) receptors per cell in control cultures and 28.8 +/- 8.1 x 10(4) receptors per cell in TGF-beta-treated cultures (p less than 0.05). It is thus suggested that TGF-beta increases the number of CTR of these cells that have other features of preosteoclasts. The role of this cytokine on the process of osteoclast differentiation and in bone resorption is thus emphasized.
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ABSTRACT: The active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], suppresses disease development in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). However, complete disease prevention only occurs with doses that dramatically elevate serum calcium levels, thus limiting the usefulness of 1,25(OH)(2)D(3) as a potential MS therapeutic agent. Because calcitonin (CT) is believed to be released by hypercalcemia and has been shown to be anti-inflammatory, we examined whether suppression of EAE by 1,25(OH)(2)D(3) could be mediated either in part or entirely by CT. Continuous administration of pharmacological doses of CT did not prevent EAE. However, a combination of CT and a subtherapeutic dose of 1,25(OH)(2)D(3) additively suppressed EAE without causing hypercalcemia. Moreover, CT decreased the dose of 1,25(OH)(2)D(3) required for disease suppression. Our results suggest that CT may be a significant factor but cannot account entirely for 1,25(OH)(2)D(3)-mediated suppression of EAE.Proceedings of the National Academy of Sciences 04/2009; 106(13):5276-81. · 9.81 Impact Factor
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ABSTRACT: Osteoclast activation is a critical cellular process for pathological bone resorption, such as erosions in rheumatoid arthritis (RA) or generalized bone loss. Among many factors triggering excessive osteoclast activity, cytokines such as IL-1 or tumour necrosis factor (TNF)-alpha play a central role. New members of the TNF receptor ligand family (namely receptor activator of nuclear factor-kappa B [RANK] and RANK ligand [RANKL]) have been discovered whose cross-interaction is mandatory for the differentiation of osteoclasts from hemopoietic precursors, in both physiological and pathological situations. Osteoprotegerin, a decoy receptor which blocks this interaction, decreases osteoclast activity and could have a fascinating therapeutic potential in conditions associated with upregulated bone resorption.Arthritis Research & Therapy 11/2000; 2(6):451-456. · 4.30 Impact Factor
Chapter: Osteoporosis[Show abstract] [Hide abstract]
ABSTRACT: Key Points • Bone health requires total nutrition, because the integrity of bone tissue depends on the integrity of its cells, which (similarly to most other tissues) need a broad array of macro- and micronutrients. Additionally, calcium and protein play key roles, because the bulk of the bony material is made up of these substances. • Bone turns over relatively slowly. Thus, the effects of inadequate nutrition on bone often are delayed, and the structural properties of bone tend to reflect past nutrition more than current intakes. • Calcium is a threshold nutrient. The minimum daily requirement is the intake at which bony response plateaus. To reach this threshold, calcium intake should be 1500 mg/d both during growth and after age 50. With lifelong calcium intakes in this range, risk of osteoporotic hip and other nonspine fractures can be reduced by 30 to 50%. • Vitamin D is predominantly produced in the skin. Recommended daily oral intakes are sufficient only to prevent the most extreme bony manifestations of vitamin D deficiency. Optimal vitamin D status is ensured by serum 25-hydroxyvitamin D [25(OH)D] values of 80 nmol/L (32 ng/mL) or more. Lower values are associated with impaired calcium absorption and increased osteoporotic fracture risk. Daily use of vitamin D may be as high as 4000 IU (100μg). For most elderly individuals, a daily oral dose of 1000 IU or higher is necessary to sustain adequate serum 25(OH)D concentrations. • Protein, once thought to be potentially harmful to bone when ingested in large quantities, is now best understood as complementary to calcium. Together, the two nutrients provide the bulk constituents of bony material; to achieve the full benefit of either, the intake of the other must be adequate as well. Protein intakes that optimize bony response are uncertain but, from available data, appear to be above the current Recommended Daily Allowance (RDA; 0.8 g/kg of body weight). • Although typical magnesium intakes are below the RDA (310 and 400 mg/d for women and men, respectively), there appear to be no skeletal consequences of the shortfall. Supplemental magnesium does not improve calcium absorption in individuals consuming typical diets and has no effect on calcium balance. • Vitamin K, zinc, manganese, and copper are involved in various aspects of bone matrix formation, but it is not known whether deficiency of any of these contributes to the development or severity of typical osteoporosis. • Recovery from hip fracture can be substantially improved with aggressive attention to the nutritional status of patients with hip fractures, with special emphasis on repairing the protein malnutrition that is common in such patients.12/2004: pages 433-460;