Bone resorption inhibitory activity

Around 99% of calcium is contained in the bones, whereas the other 1% resides in the extracellular fluid. Of this extracellular calcium, approximately 40% is bound to albumin, and the remainder is in the ionized, physiologically active form. Normal calcium levels are maintained by three primary factors parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin. Parathyroid hormone increases renal tubular calcium resorption and promotes bone resorption. The active form of vitamin D, 1,25-dihydroxyvitamin D, regulates absorption of calcium from the GI tract. Calcitonin serves as an inhibitory factor by suppressing osteoclast activity and stimulating calcium deposition into the bones. 

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... 

The early stages of bone pathology in rheumatoid disease manifest as periarticular osteoporosis and juxta-articular bone erosion. Osteoclast overactivity is the predominant influence in such bone erosion and NO has a direct inhibitory efiect on osteoclastic bone resorption (MacIntyre et al., 1991). Endothelial cells, present in abundance and in close proximity to the osteoclast may therefore play a role in down-regulating osteoclast activity through the production of NO. Since the osteoclast is of macrophage lineage, it is likely to be... 

Interleukin 1 (IL-1) is produced mainly by activated monocytes-macropha-ges, and its principal action is to stimulate thymocytes. A pleiotropic cytokine, IL-1 induces the expression of a large diversity of cytokines such as IL-6, leukaemia inhibitory factor (LIF), and other proinflammatory molecules (Di-marello 1994). IL-1 and TNF-a carry out as part of their function increasing the expression of NF-/cB and JNK (c-Jun N-terminal kinase). The importance of IL-1 in OCS is demonstrated because the IL-1-receptor-deficient mouse is resistant to ovariectomy (OVX)-induced bone loss (Lorenzo et al. 1998). The importance in pathological bone loss is also illustrated by the fact that treatment with IL-1 receptor antagonist slows down bone erosion for patients affected with rheumatoid arthritis (Kwan et al. 2004). IL-1 increases osteoclast differentiation rather than mature osteoclast activity, and infusion of IL-1 into mice induces hypercalcemia and bone resorption. Finally, IL-1 and TNF-a... 

Palmqvist P, Persson E, Conaway HH, Lerner UH (2002) IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 169 3353-3362... 

Several tetracyclines with collagenase inhibitory activity have also been shown to inhibit parathyroid-induced bone resorption in organ culture [229]. Subsequent experiments with CI-1 have reinforced the view that a collagenase is involved in bone resorption and, in fact, the resorption of demineralized collagen by collagenase may be the rate-limiting step [230,231 ]. 

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. 

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... 

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. 

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. 

Cathepsins comprise a family of enzymes within the papain superfamily of cysteine proteases that play important roles in physiological processes such as bone resorption, tumor metathesis, and rheumatoid arthritis. Recently we reported a series of novel compounds which exhibit potent inhibitory activity against cathepsin L. To explore further this novel class, we have constructed a library of thiocarbazates and tested them against a panel of serine and cysteine proteases. Preliminary studies reveal that some of these compounds are highly selective for cathepsin S over B and L, with nanomolar IC50 values. The results of these studies will be described. 

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. 

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