Changes of serum soluble receptor activator for nuclear factor-κB ligand after glucocorticoid therapy reflect regulation of its expression by osteoblasts.

CONTEXT 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. PATIENTS AND 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. CONCLUSION Serum soluble RANKL might be a useful marker of bone remodeling in patients with systemic autoimmune diseases receiving glucocorticoid therapy.

[1]  W. Lems,et al.  Glucocorticoid-induced osteoporosis. , 2011, Clinical and experimental rheumatology.

[2]  D. Findlay,et al.  Relationship between serum RANKL and RANKL in bone , 2011, Osteoporosis International.

[3]  M. Maricic.  Update on glucocorticoid-induced osteoporosis. , 2011, Rheumatic diseases clinics of North America.

[4]  M. Cutolo.  Vitamin D and autoimmune rheumatic diseases. , 2008, Rheumatology.

[5]  N. Maalouf,et al.  The Role of Receptor Activator of Nuclear Factor-κB (RANK)/RANK Ligand/Osteoprotegerin: Clinical Implications , 2007 .

[6]  J. Williams,et al.  Effects of dissociated glucocorticoids on OPG and RANKL in osteoblastic cells. , 2006, Bone.

[7]  R. Eastell,et al.  Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. , 2005, The Journal of clinical endocrinology and metabolism.

[8]  G. Burmester,et al.  Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. , 2004, Arthritis and rheumatism.

[9]  L. Hofbauer,et al.  The OPG/RANKL/RANK system in metabolic bone diseases. , 2004, Journal of musculoskeletal & neuronal interactions.

[10]  W. Kratzer,et al.  Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn's disease , 2003, European journal of gastroenterology & hepatology.

[11]  Y. Asano,et al.  Changes in osteoprotegerin and markers of bone metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis. , 2002, Bone.

[12]  C. Hwang,et al.  Deflazacort increases osteoclast formation in mouse bone marrow culture and the ratio of RANKL/OPG mRNA expression in marrow stromal cells. , 2001, Journal of Korean medical science.

[13]  D. Lacey,et al.  Stimulation of Osteoprotegerin Ligand and Inhibition of Osteoprotegerin Production by Glucocorticoids in Human Osteoblastic Lineage Cells: Potential Paracrine Mechanisms of Glucocorticoid-Induced Osteoporosis1. , 1999, Endocrinology.

[14]  C. O’Brien,et al.  STAT3 Activation in Stromal/Osteoblastic Cells Is Required for Induction of the Receptor Activator of NF-κB Ligand and Stimulation of Osteoclastogenesis by gp130-utilizing Cytokines or Interleukin-1 but Not 1,25-Dihydroxyvitamin D3 or Parathyroid Hormone* , 1999, The Journal of Biological Chemistry.

[15]  T. Martin,et al.  Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. , 1999, Endocrine reviews.

[16]  C. Ohlsson,et al.  Osteoprotegerin mRNA is expressed in primary human osteoblast-like cells: down-regulation by glucocorticoids. , 1998, The Journal of endocrinology.

[17]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[18]  K Yano,et al.  Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Dubose,et al.  A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function , 1997, Nature.

[20]  T. Vischer,et al.  Elevated serum levels of interleukin-1 receptor antagonist in polymyositis/dermatomyositis. A biologic marker of disease activity with a possible role in the lack of acute-phase protein response. , 1994, Arthritis and rheumatism.

[21]  P. Feng,et al.  C-reactive protein and serological indices of disease activity in systemic lupus erythematosus. , 1983, Annals of the rheumatic diseases.

[22]  Yoshiya Tanaka,et al.  Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research: 2014 update , 2014, Journal of Bone and Mineral Metabolism.

[23]  R. Kitazawa,et al.  Dexamethasone promotes osteoclastogenesis by inhibiting osteoprotegerin through multiple levels , 2008, Journal of cellular biochemistry.

[24]  M. Fukunaga,et al.  Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research (2004) , 2004, Journal of Bone and Mineral Metabolism.

[25]  Tomoki Shiozawa,et al.  Changes in bone turnover markers during 14-day 6° head-down bed rest , 2003, Journal of Bone and Mineral Metabolism.

[26]  J. Penninger,et al.  RANK-L and RANK: T cells, bone loss, and mammalian evolution. , 2002, Annual review of immunology.

[27]  Stuart Ra,et al.  Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disorders. , 1995 .