Study on mechanism of the coupling between bone resorption and bone formation

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Aim of the study :The discovery of RANKL elucidates the mechanism of osteoclast differentiation and function regulated by osteoblasts. Osteoprotegerin (OPG), a soluble decoy receptor of RANKL, inhibits both differentiation and function of osteoclasts. OPG-deficient (OPG-/-) mice exhibited severe osteoporosis caused by enhanced osteoclastic bone resorption. Deficiency of OPG in human has been shown to result in juvenile Paget's disease. The previous morphological study showed that osteoblastic bone formation was activated in OPG-/-mice. These results suggest that osteoclastic bone resorption coincidentally induces osteoblastic bone formation by an unknown factor (called coupling factor). In the present study, we examined a possibility that mature osteoclasts produce cytokines which influence bone metabolism using mature osteoclasts treated with LPS. Using OPG -/-mice, we also explored whether such a coupling factor is present in bone in OPG -/-mice.Results :(1)p38MAP kinase was essentia … More lly involved in the differentiation of bone marrow macrophages (osteoclast precursors) into osteoclasts. The p38MAP kinase-signaling pathway was all dead in mature osteoclasts. (2)Mature osteoclasts were shown to produce an osteoblast-activating factor but not bone-resorbing cytokines such as IL-1 and IL-6 in response to LPS. (3)Blood levels of osteocalcin and ALP of OPG-/-mice were markedly increased in OPG-/-mice. Bone histomorphometric studies showed that both bone resorption and bone formation were activated in OPG-/-mice. (4)Serum levels of soluble RANKL were also elevated in OPG-/-mice. (5)When 1,25(OH)_2D_3 was administered into OPG -/-and wild-type mice, serum RANKL concentrations were markedly increased in OPG-/-mice but not in wild-type mice. (6)OPO -/-osteoblasts released a large amount of RANKL in the culture medium, which was completely inhibited by adding OPG (7)When bisphosphonate (risedronate) was injected into OPG -/-mice, bone formation -related parameters as well as bone resorption-related parameters were sharply decreased in the treated mice. (8)Treatment of OPG -/-mice with risedronate decreased serum osteocalcin and ALP levels but not the serum RANKL level. (9)Ectopic bone formation induced by BMP is not accelerated in OPG -/-mice.Conclusion :These results suggest (1)that mature osteoclast produce a coupling factor but not bone resorbing factors, and (2)that bone resorption is tightly coupled with bone formation at the sites where borne resorption takes place. Less