in these cells, compared with the control serum. Since BMP-2 induces ectopic bone and cartilage formation in extraskeletal tissues in vivo and activates AVCR1, the present data suggest the possibility that there might be some serum soluble factors, which enhancing muscle ossification in the FOP patient.

Bone resorption and bone formation indices are increased and decreased in this FOP patient. The use of glucocorticoid and long-term immobilization might enhance bone resorption. The direct action of glucocorticoid on the gene expression in skeletal cells plays the main role in glucocorticoid-induced osteoporosis (GIO). In GIO, glucocorticoid induces a decrease in osteoblastgenesis and an increase in the apoptosis of mature osteoblast and osteocyte, by inhibiting the expression of osteoblastic key genes, resulting in osteoblastic bone formation [12].

Immobilization induces bone loss, since the reduction of compressive mechanical forces during immobilization results in stimulating osteoclast activity by inducing bone resorption factors, such as receptor activator of NF-κB ligand [13]. In this patient, the long-term immobilization state might enhance bone resorption, leading to an increase of bone resorption indices in spite of glucocorticoid administration. The change of some soluble factors in the serum of this patient by glucocorticoid use and immobilization might be responsible for enhancing the level of ALP, OCN and BMP-2 in osteoblast. Furthermore, increased bone resorption indices may be due to BMP-2, stimulation of bone resorption by enhanced osteoclast formation, and osteoclastic activity [14,15]. Okamoto et al. [16] reported that mice overexpressing BMP- 4 in bone developed severe osteopenia with increased osteoclast number. Enhanced BMP activity itself might be one of the causes of enhanced bone resorption indices in this FOP patient.

The serum was obtained before taking 0.75 mg betamethazone in the morning, 24 hr after administration the previous day. Serum concentration of betamethasone, the next morning, was considered to be very low, since Miyachi et al. reported that betamethazone in the serum disappeared 24 hr after oral administration, otherwise the patient developed liver failure [17]. These findings indicate that the residual betamethasone did not modulate the effects of serum from the FOP patient in the present study.

5. Conclusion

We presented a case of FOP with progressive ossification in extra-skeletal tissues with ACVR1 mutation. This mutation was responsible for the pathogenesis in this patient. From the present data, a systemic humoral factor may be related to the pathogenesis of FOP in this patient. Some bone anabolic factors might be elevated in the serum from the patient with FOP. Alternatively, some inhibitory factors for bone formation could be suppressed in the patient serum. Moreover, the effects of the patient serum on ALP, OCN and BMP-2 should be confirmed in several patients with FOP. Further studies are necessary to clarify this issue and will be performed in the near future.

6. Acknowledgements

We greatly thank Yoshiko Higashimaki and Erika Matsumoto for expert technical assistance. This work was supported in part by a grant from a grant-in-aid (21591179) from the Ministry of Science, Education, and Culture of Japan (to H.K), the Global COE Program F11 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.


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