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
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.