Diacerein reduces the excess synthesis of bone remodeling factors by humanosteoblast cells from osteoarthritic subchondral bone

Citation
Jp. Pelletier et al., Diacerein reduces the excess synthesis of bone remodeling factors by humanosteoblast cells from osteoarthritic subchondral bone, J RHEUMATOL, 28(4), 2001, pp. 814-824
Citations number
48
Categorie Soggetti
Rheumatology,"da verificare
Journal title
JOURNAL OF RHEUMATOLOGY
ISSN journal
0315162X → ACNP
Volume
28
Issue
4
Year of publication
2001
Pages
814 - 824
Database
ISI
SICI code
0315-162X(200104)28:4<814:DRTESO>2.0.ZU;2-A
Abstract
Objective. Although cartilage degradation characterizes osteoarthritis (OA) , there is evidence that remodeling of subchondral bone in this disease is a contributing factor. Therapeutic strategies to modify the metabolism of s ubchondral bone osteoblasts may be indicated to treat OA. We studied the ef fects of diacerein and rhein on the metabolic and inflammatory variables of OA subchondral osteoblasts. Methods. Human OA primary subchondral osteoblast cells were used. The effec t of diacerein and rhein at therapeutic concentrations (5-20 mug/ml) was de termined by osteoblast phenotypic factors, alkaline phosphatase, osteocalci n, and cAMP: on metabolic agents urokinase plasminogen activator (uPA), pla sminogen activator inhibitor-1 (PAI-I), and insulin-like growth factor-1 (I CF-I); and on inflammatory mediators interleukin 6 (IL-6), prostaglandin E- 2 (PGE(2)), and cyclooxygenase-2 (COX-2). Results. Diacerein and rhein did not affect either basal and 1,25(OH)(2)D-3 induced alkaline phosphatase or parathyroid hormone (PTH) stimulated cAMP formation. Conversely, they dose dependently and statistically inhibited 1. 25(OH)(2)D-3 induced osteocalcin release, a situation explained by a reduct ion of mRNA levels for osteocalcin. Of the metabolic factors, they inhibite d the production of uPA, with rhein showing slightly more potency; inhibiti ons of 69% and 57% were reached at the highest concentration (20 mug/ml) of rhein and diacerein, respectively. Both drugs also inhibited the PAI-1 lev el. albeit at a much lower level than for uPA. Interestingly, determination of the uPA/PAI-1 ratio revealed that both drugs inhibited it about 55%, su ggesting a decrease in uPA activity. In contrast, IGF-I levels only increas ed slightly when cells were treated with rhein but not with diacerein. A tr ansient dose dependent effect was found on IL-6 production; an inhibition w as noted at low drug concentrations, which returned to basal levels at the highest concentration tested. PGE(2) levels increased exponentially and wer e related to a concomitant increase in COX-2 levels in response to both dru gs. Conclusion, Our data indicate that diacerein and rhein do not appear to aff ect OA subchondral bone cells' basal cellular metabolism, yet both agents r eveal a direct effect at reducing the synthetic activities of osteoblasts. which could be responsible for abnormal subchondral bone remodeling occurri ng during the course of OA.