Bone resorption inhibitory effect

Baba et al. [286,287] studied the structure-activity relationships of some lignans as anti-inflammatory agents and in a second paper gave detailed information on the bone resorption inhibitory effects of these compounds. Chemical modification of the potent bone resorption inhibitor justicidin was performed and various naphthalene lactones, quinoline lactones and... 

To clarify the mechanism of action of these diterpenoids on bone resorption, their effect on osteoclast-like cell formation was tested according to the method reported by Takahashi et al.[34]. As a result, both compounds dose-dependently inhibited PTH-induced tartrate resistant acid phosphatase-positive MNC formation. Especially, SDC showed complete inhbition at concentration over 0.1 pM. Next, the effect of SDB and SDC on resorbing activity of osteoclasts (pit forming activity of osteoclast-like cells) was assayed according to the method of Tamura et al. [35]. As indicated in Table 8, both compounds inhibited the pit-formation when osteoclasts obtained by the co-culture were placed on dentine slice in the presence of these compounds. Therefore, the inhibitory effect of... 

YAMAGUCHI M and GAO Y H (1998) Inhibitory effect of genistein on bone resorption in tissue culture. Biochem Pharmacol 55, 71-6. 

The most extensively used animal model to evaluate the action of SERMs on bone has been the ovariectomized (OVX) rat. In rats, tamoxifen antagonizes bone resorption and uterine growth (Turner et al. 1987,1988) and reduces the number and size of osteoclasts. The inhibitory effect on bone resorption of tamoxifen has also been reported in dogs and immobilized male rats (Wakley et al. 1988 Waters et al. 1991). As an antiresorptive agent, however, tamoxifen is less effective than 17/3-estradiol (17/9E2) (Williams et al. 1991) and has no effect when the endogenous production of estrogens is normal (Evans et al. 1994). 

A role for a collagenase, presumably fibroblast-type collagenase, in bone resorption has been indicated by studies employing the Searle A-carboxyl alkyl synthetic collagenase inhibitor CI-1 (compound (197) in Table 8.18) and its less potent stereoisomer CI-2 (compound (198) in Table 8.18) [207]. Cultured embryonic mouse calvaria treated with parathyroid hormone exhibit loss of calcium and show pronounced collagen resorption. CI-1 inhibited the collagen resorption in a dose-dependent manner at significantly lower concentrations than CI-2, but had only a small effect on calcium loss. This inhibitory effect was reversible and not due to inhibitor cytotoxicity. 

AP23451 administration to mice inoculated with MDA-231 breast cancer cells effectively prevents metastasis-induced osteolysis similar to bisphosphonate zoledronic (Zometa ). However, it also significantly reduces the volirme of tumor cells inside the bone marrow cavities of the mice as opposed to a lack of inhibitory effect on tirmor cell volume in mice treated with zoledronic acid. AP23588 is also a bone-targeted Src kinase inhibitor which has been determined to possess both anti-resorptive and anabohc properties in vitro with respect to reducing osteoclast activity and stimulating osteoblast activity, respectively. 

Zaidi M, Kerby J, Huang C.-H, Alam ASMT, Rathod H, Chambers TJ, Moonga BS. 1991. Divalent cations mimic the inhibitory effects of extracellular ionized calcium on bone resorption by isolated rat osteoclasts Further evidence for a calcium receptor . J Cell Physiol 149 422-7. 

Staal, A., Frith, J.C., French, M.H., Swartz, J., Gungor, T., Harrity, T.W., Tamasi, J., Rogers, M.J., and Feyen, J.H. (2003). The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. J Bone Miner Res 18 88-96. 

Our studies on biologically active substances of this plant led to isolation of diterpenoids showing cytotoxicity [8], inhibitory effects on fi-glucuronidase [9], H+,K+-ATPase [10-12], replication of herpes simplex virus type 1 (HSV-1) [8,13,14] and bone resorption stimulated by parathyroid hormone (PTH) [15], and antitumor [16] and antitumor promoting effects [17]. In addition, some flavonoids possessing cytotoxicity [18], inhibitory activity against [3-glucuronidase [19] and antiviral activity [20] were also obtained from whole plants. 

As described above, SDB and SDC showed interesting biological effects, i.e., inhibitory effects on cell proliferation, replication of HSV-1, H+,K+-ATPase and PTH-stimulated bone resorption. In order to evaluate further these ditepenoids as medicinal agents, some structure-activity relationships were investigated. The test samples were obtained mainly by chemical modification of SDB and SDC. Some synthetic intermediates obtained in the total synthesis of SDA and SDB by Overman et al. were also tested. Structures of the test samples are shown in Fig. (7) and Table 12. 

A total of twenty one compounds were tested for their inhibitory effects on PTH-stimulated bone resorption. Table 15 shows the summary of the... 

Table IS. Inhibitory effect of SDB and its derivatives on bone resorption...

SDB and SDC, scopadulan-type diterpenoids, showed cytotoxicity, anti-HSV-1 activity and inhibitory effects on histamine-induced gastric acid secretion and PTH-stimulated bone resorption. 

Postmenopausal bone loss is effectively inhibited by prophylactic administration of estrogen (Recker et al, 1977), but estrogen administration to osteoporotic patients (the conventional treatment) fails to restore lost bone. Estrogen appears to act primarily by putting a brake on bone resorption, i.e., it inhibits the action of parathyroid hormone, the primary stimulus to osteoclastic bone resorption. The mechanism of this inhibition is unknown receptors for estrogen have not been found in bone. A high intake of calcium during the postmenopausal period (up to 1500 mg/d) also is inhibitory (Heaney, 1981), presumably because it raises the level of ionized calcium in the serum sufficiently to suppress parathormone synthesis. 

Etidronate, clodronate, and several other hrst-generation bisphosphonates had been shown to inhibit vitamin D-induced artery calcification in rats." This was thought to be due to the inhibitory effect of bisphosphonates on formation of hydroxyapatite crystals. Later, alendronate and ibandronate were demonstrated to inhibit warfarin-induced calcification of arteries and heart valves in rats at doses comparable to the doses that inhibit bone resorption. However, in a randomized trial of fifty patients with stage 3-4 chronic kidney disease comparing weekly alendronate to placebo, there was no difference in vascular calcification progression assessed by computed tomography with alendronate compared with placebo. ... 

Hydroxy 1,4-dimethyl carbazoie has a pronounced inhibitory effect on lipid peroxidation 109). Inhibition of resorption in organ culture of fetal rat long bones was found using carbazoie-1-carboxylic acid as a test material 103). 

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