Transforming growth factor-? 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
Transforming growth factor-β (TGF-β) 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-β enhanced the proportion of cells expressing the VNR.
In the present study, we investigated the effect of TGF-β 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-β (500 pg/ml) significantly decreased the cell protein content. TGF-β alone did not stimulate basal cAMP production. The 10 nM-sCT-stimulated cAMP production was enhanced by increasing TGF-β concentrations from 50 pg/ml to 1,000 pg/ml: for 500 pg/ml TGF-β, it was 294 ± 28% vs. 140 ± 25% for control cultures (p < 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-β than in control cultures. The increase was 325 ± 36% in the presence of TGF-β and 195 ± 13% in the absence of TGF-β, for 10−7 M sCT (p < 0.01). This effect of TGF-β 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-β-treated cells. By contrast, the CTR number was significantly increased in the presence of TGF-β: 6.1 ± 2 × 104 receptors per cell in control cultures and 28.8 ± 8.1 × 104 receptors per cell in TGF-β-treated cultures (p < 0,05). It is thus suggested that TGF-β 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.
"Conversely, some cytokines such as IL-4 or IFN-γ have been shown to inhibit osteoclast differentiation in vitro . The role of transforming growth factor-β is more complex; it decreases osteoclast precursor proliferation and bone resorption activity [17,18], but it also increases the expression of two osteoclastic markers — vitronectin receptor and calcitonin receptor [19,20]. Most of the cytokines that regulate osteoclast differentiation are produced in the bone microenvironment, mainly by osteoblast/stromal cells, further emphasizing the key role of these cells in osteoclast differentiation. "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: The peptide calcitonin (CT) was initially discovered in 1962 as a novel hypocalcemic hormone. This hypocalcemic response was principally due to a potent inhibitory action of CT on osteoclast mediated bone resorption and it is this action which underlies its widespread clinical use for the treatment of bone disorders, including Paget's disease, osteoporosis and hypercalcemia of malignancy. In this article we review the basic physiology of CT action, structure-function studies on CT peptides, cloning of CT receptors and the identification of isoforms of the receptor derived from alterative splicing of the receptor mRNA. We also review the state of understanding on CT receptor mediated signaling and receptor regulation, along with developing concepts of how CT peptides interact with the receptor, including how the receptors may interact with receptor activity modifying proteins to produce novel phenotypes. Finally, current therapeutic use is reviewed, and the potential for expanded use that may come with advances in delivery of peptides or CT mimetics.
Current Medicinal Chemistry 12/1999; 6(11):1067-93. · 3.85 Impact Factor
[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.
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