Molecular and Cellular PharmacologyCurcumin suppresses increased bone resorption by inhibiting osteoclastogenesis in rats with streptozotocin-induced diabetes
Introduction
Insulin-dependent diabetes mellitus is associated with decreased bone mass and osteoporosis (Krakauer et al., 1995, Tuominen et al., 1999, Kemink et al., 2000). Streptozotocin-induced diabetes in rats is a well-recognized model of insulin-dependent diabetes mellitus (Szkudelski, 2001). The effects of insulin-dependent diabetes mellitus have generally been attributed to insulin deficiency and to an impairment in osteoblastic function since insulin has a stimulatory effect on osteoblasts. However, increases in markers of osteoclastic function such as the excretion of calcium, hydroxyproline, and deoxypyridinoline in urine were reported in subjects with insulin-dependent diabetes mellitus (Selby et al., 1995, Bjorgaas et al., 1999). In fact, we have reported increases in the expression of cathepsin K and tartrate-resistant acid phosphatase (TRAP) at the early stages of streptozotocin-induced diabetes in rats (Hie et al., 2007). The increase in osteoclastic activity associated with the decreased osteoblastic activity leads to a diabetic osteopenia later on. The suppression of the increased bone resorptive activity at the early stages of diabetes would be useful for preventing, or at least delaying, the later loss of bone mass.
Bone resorption is carried out by hematopoietically derived osteoclasts (Udagawa et al., 1990, Kurihara et al., 1990). Their number and activity is determined by cell lineage allocation, the proliferation and differentiation of osteoclast precursors and the resorptive efficacy of mature osteoclasts (Harada and Rodan, 2003). Osteoclastic differentiation which requires macrophage colony-stimulating factor (M-CSF) and receptor for activation of NF-κB ligand (RANKL) is a multi-step process that eventually leads to the expression of TRAP, multinucleation, and bone-resorbing activity (Boyle et al., 2003, Asagiri and Takayanagi, 2007). The binding of M-CSF to c-Fms stimulates the expression of RANK in the hematopoietic osteoclast precursor cells. The binding of RANKL to its receptor RANK activates NF-κB and activator protein-1(AP-1) in osteoclast precursors and induces osteoclastic differentiation (Asagiri and Takayanagi, 2007). From a clinical point of view, the RANKL signaling pathway has promise as a strategy for suppressing excessive osteoclastic formation.
Curcumin (diferuloyl methane), a polyphenolic phytochemical, is a primary component of the dietary spice tumeric. It has been used for centuries in indigenous medicine for the treatment of a variety of inflammatory conditions and other diseases (Ammon and Wahl, 1991). Curcumin has been demonstrated to be a powerful inhibitor of AP-1 (Hanazawa et al., 1993, Bierhaus et al., 1997, Chen and Tan, 1998, Squires et al., 2003). The transcription factor AP-1, a dimeric complex composed of Fos and Jun, is activated by RANKL and induces the expression of osteoclast-specific genes. c-Fos is crucial for AP-1 interaction with its specific transcriptional partner, which is required in osteoclastogenesis. Mice expressing an inactivated c-fos or deficient in c-fos manifested arrested osteoclastic development and osteopetrosis (Wang et al., 1992, Grigoriadis et al., 1994). These findings suggest a potential role for curcumin in treatment for preventing bone resorptive activity.
In the present study, we examined the effects of a dietary supplement of curcumin on the stimulated osteoclastic activity and demonstrated that curcumin inhibited bone resorptive activity with the suppression of osteoclastogenesis in rats with streptozotocin-induced diabetes.
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Animals and study design
Ten-week-old female rats of the Wistar/ST strain were purchased from Japan SLC (Shizuoka, Japan) and housed individually in a temperature-controlled room with a 12-h light cycle. After fasting overnight, sixteen rats were treated with streptozotocin (45 mg/kg body weight in 0.05 M citrate buffer, pH 4.5, i.p.), a pancreatic beta-cell cytotoxin, to render them diabetic. Eight control animals received the same volume of the streptozotocin diluent. The diagnosis of diabetes was based on glycosuria
Streptozotocin-induced diabetes and effects of curcumin on glucose levels in urine and serum, food intake, body weight, and bone length and weight
The injection of streptozotocin increased glucose levels in urine before the curcumin supplement was given (at 4 days after the Streptozotocin-injection) (Table 1). The diabetic status induced by streptozotocin persisted throughout the study period as evidenced by hyperglycemia, high water intake, high food intake and polyuria. The curcumin supplement did not affect the serum glucose levels and food intakes of diabetic rats.
Body weight (final) and bone weights of the femur, tibia and distal
Discussion
This study clearly demonstrated that the dietary supplement of curcumin suppressed the increased bone resorptive activity in rats with streptozotocin-induced diabetes. Consistent with previous findings at 1 week after the injection of streptozotocin (Hie et al., 2007), the TRAP and cathepsin K activity in the distal femoral bone increased at 2 weeks. In diabetic rats, the elevated level of cathepsin K activity stimulated degradation of the bone matrix, resulting in a decrease in the amount of
Acknowledgment
This work was supported in part by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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