[Anabolic effects and inhibition of interleukin 6 production induced by neridronate on human osteoblasts].
Bisphosphonates (BPs) are pharmacological compounds widely used in the treatment of a variety of bone-related diseases, particularly where the bone-turnover is skewed in favour of osteolysis. The mechanisms by which BPs reduce bone-resorption directly acting on osteoclasts (OCs) are now largely clarified even at molecular level. The researches concerning the BPs effects on osteoblasts (OBs) have instead shown variable results.


OBJECTIVE
We have investigated the efficacy of neridronate (NER), an amino-BP, as anabolic agent on human OBs. Moreover, we have tried to verify if NER is able to negatively modulate the production of IL-6 on OBs stimulated or not by the pro-inflammatory cytokine IL-1beta.


METHODS
We have tested if different concentrations of NER (from 10-11 M to 10-3 M), added to primary human OB cultures, could affect the cells number, the endogenous cellular alkaline phosphatase (ALP) activity, the collagen I (COL-I) synthesis, the formation of mineralized nodules and the IL-6 production. Our experimental approach was performed testing a wide range of NER concentrations because, under physiological conditions, OBs seems to be exposed to variable and transient levels of the drug.


RESULTS
Our results show that NER doesn't negatively affect in vitro the viability, proliferation and cellular activity of human OBs, even after 20 days of exposure to concentrations < or =10-5 M (therapeutic dose). In addition, NER seems to enhance the differentiation of cultured OBs in mature bone-forming cells. A maximum increase of COL-I synthesis (+25% after 4 days; p < 0.05), ALP activity (+50% after 10 days; p < 0.01) and mineralized nodules (+48% after 20 days; p < 0.05) was observed in cultures treated with NER 10-8 M. A maximal reduction of IL-6 secretion (-24% on IL-1beta stimulated cultures and -29% on unstimulated cultures) was observed for NER 10-9 M.


CONCLUSIONS
These results encourage the use of neridronate in therapy of demineralizing metabolic bone disorders.
Spreafico
A
A
Dipartimento di Medicina Clinica e Scienze Immunologiche, Sezione di Reumatologia, Università di Siena, Italia. spreafico@unisi.it
Frediani
B
B
Capperucci
C
C
Gambera
D
D
Ferrata
P
P
Baldi
F
F
Chellini
F
F
Niccolini
S
S
Bocchi
L
L
Marcolongo
R
R
D000368:Aged; D001851:Bone Diseases, Metabolic / Q000188:drug therapy; D016207:Cytokines; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
D016207:Cytokines; D004164:Diphosphonates; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C053389:6-amino-1-hydroxyhexane-1,1-diphosphonate