Changes of serum soluble receptor activator for nuclear factor-κB ligand after glucocorticoid therapy reflect regulation of its expression by osteoblasts.
BACKGROUND
Osteoporosis is a serious complication of systemic glucocorticoid therapy. The role of serum soluble receptor activator for nuclear factor-κB ligand (RANKL) in glucocorticoid-induced osteoporosis remains unclear.


OBJECTIVE
The objective of the study was to clarify the influence of serum soluble RANKL on the osteoprotegerin (OPG)/RANKL/receptor activator for nuclear factor-κB system in patients with systemic autoimmune diseases receiving glucocorticoid therapy.


METHODS
Sixty patients (40 women) with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60 mg/d) plus bisphosphonate therapy were prospectively enrolled. Serum soluble RANKL and OPG levels were measured at 0, 1, 2, 3, and 4 wk after starting glucocorticoid therapy. The effects of dexamethasone on production of RANKL and OPG mRNA and protein by cultured normal human osteoblasts were evaluated by RT-PCR and ELISA, respectively.


RESULTS
The mean serum soluble RANKL level of the patients was unchanged by glucocorticoid therapy. Because the distribution of serum soluble RANKL was bimodal, the patients were stratified into two groups. Serum soluble RANKL decreased significantly in the higher soluble RANKL group (≥0.16 pmol/liter), whereas it increased significantly in the lower soluble RANKL group. The mean serum OPG level of the patients decreased significantly. Bone mineral density increased in the higher soluble RANKL group after starting glucocorticoid therapy, whereas it decreased in the lower soluble RANKL group. In cultures of unstimulated human osteoblasts, RANKL mRNA expression was increased and OPG mRNA was decreased by dexamethasone. Up-regulation of RANKL and OPG mRNA by IL-6 was suppressed by dexamethasone.


CONCLUSIONS
Serum soluble RANKL might be a useful marker of bone remodeling in patients with systemic autoimmune diseases receiving glucocorticoid therapy.
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan.
Kaichi
K
Kaneko
Natsuko
N
Kusunoki
Tomoko
T
Hasunuma
Shinichi
S
Kawai
D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D011239:Prednisolone / Q000008:administration & dosage; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
D015415:Biomarkers; D005938:Glucocorticoids; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; C505688:TNFSF11 protein, human; D011239:Prednisolone