Increased RANK ligand in bone marrow of orchiectomized rats and prevention of their bone loss by the RANK ligand inhibitor osteoprotegerin (original) (raw)
Related papers
RANKL/OPG; Critical role in bone physiology
Reviews in Endocrine and Metabolic Disorders, 2015
After it was proposed that the osteoblast lineage controlled the formation of osteoclasts, cell culture methods were developed that established this to be the case. Evidence was obtained that cytokines and hormones that promote osteoclast formation act first on osteoblast lineage cells to promote the production of a membrane-bound regulator of osteoclastogenesis. This proved to be receptor activator of NF-kB ligand (RANKL) a member of the tumor necrosis factor ligand family that acts upon its receptor RANK in the hematopoietic lineage, with interaction restricted by a decoy soluble receptor osteoprotegerin (OPG), also a product of the osteoblast lineage. The physiological roles of these factors were established through genetic and pharmacological studies, have led to a new physiology of bone, with complete revision of older ideas over the last 15 years, ultimately leading to the development of new pharmaceutical agents for bone disease.
Soluble RANKL Induces High Bone Turnover and Decreases Bone Volume, Density, and Strength in Mice
Calcified Tissue International, 2008
Receptor activator for nuclear factor-j B ligand (RANKL) is an essential mediator of osteoclastogenesis. We hypothesized that administration of soluble RANKL to mice would result in high turnover and deleterious effects on both cortical and trabecular bone. For 10 days, 10-week-old C57BL/6J female mice (n = 12/ group) were given twice-daily subcutaneous injections of human recombinant RANKL (0.4 or 2 mg/kg/day) or inert vehicle (VEH). Bone turnover was greatly accelerated by RANKL, as evidenced by the 49-84% greater levels of serum TRAP-5b (bone resorption marker) and 300-400% greater levels of serum alkaline phosphatase (bone formation marker). RANKL resulted in significantly greater endocortical bone erosion surface (79-83%) and periosteal bone formation rate (64-87%) vs. VEH. Microcomputed tomographic (microCT) analysis of the proximal tibia indicated a reduction in trabecular volume fraction (-84%) for both doses of RANKL. Cortical bone geometry and strength were also negatively influenced by RANKL. MicroCT analysis of the femoral diaphysis indicated significantly lower cortical bone volume (-10% to -13%) and greater cortical porosity (8-9%) relative to VEH. Biomechanical testing of the femur diaphysis revealed significantly lower maximum bending load (-19% to -25%) vs. VEH. Bone strength remained correlated with bone mass, independent of RANKL stimulation of bone turnover. These findings are consistent with the hypothesis that soluble RANKL could be an important etiologic factor in pathologic bone loss. RANKL also has potential utility as a model for studying the consequences of high bone turnover on bone quality and strength in animals.
Brazilian Oral Research, 2014
The aim of this study was to evaluate the resorption process during the repair of autogenous bone grafts with or without coverage by an expanded polytetrafluoroethylene (e-PTFE) membrane in female rats with estrogen deficiency using the immunohistochemical technique. Eighty female rats were randomly divided into two groups (OVX and SHAM). The 40 female rats in the OVX group were subjected to ovariectomy, and the 40 female rats in the SHAM group were subjected to simulated ovariectomy. The two groups were further divided in subgroup E, which was subjected to surgery for placement of autogenous bone graft (ABG), and subgroup ME, in which the ABG was covered with an e-PTFE membrane. The animals were killed at 0, 7, 21, 45 and 60 days. The specimens were analyzed using immunohistochemistry for the bone resorption markers RANK, RANK-L and Osteoprotegerin (OPG). A higher remodeling rate was observed at 7 and 21 days after the autogenous bone grafts, when the markers were more intensely expressed. At the final time point, the specimens presented similar characteristics to those observed at the initial time point. The expression of immunohistochemical markers was not altered by the estrogen deficiency. The presence of the e-PTFE membrane delayed the bone resorption process, influencing the immunohistochemical expression of markers.
Journal of Bone and Mineral Research, 2000
Hypogonadism is considered to be one of the major risk factors for osteoporosis in men. However, the mechanisms of bone loss caused by androgen deficiency are still unclear. In the present study, we sequentially investigated the skeletal and hormonal effects of androgen deficiency in aged orchiectomized (ORX) rats over a time period of 9 months. One hundred seventy 13-month-old male Fischer-344 rats were either ORX or sham-operated (SHAM). Eight rats served as baseline controls. After in vivo fluorochrome labeling, groups of 8 -15 SHAM and ORX rats each were killed at 2 weeks and at 1, 2, 3, 4, 6, and 9 months postsurgery. As expected, ORX induced a fall in serum total and free testosterone levels, but also reduced serum estradiol concentrations. Cancellous bone area (BAr) in the proximal tibia but not in the first lumbar vertebral body showed an age-dependent decline in SHAM rats. Relative to SHAM controls, ORX rats had significantly reduced cancellous BAr after 2 weeks post-ORX in the tibia and after 2 months post-ORX in the vertebral body. Thereafter, vertebral and tibial cancellous BAr continued to decline in ORX animals throughout the study. Osteoclast number (NOc), osteoblast surface, bone formation rate (BFR), and activation frequency were increased in ORX animals from 1 month postsurgery until the end of the trial. Moreover, in close temporal association with the histomorphometric findings, serum osteocalcin and urinary excretion of collagen crosslinks and calcium were elevated in ORX rats. In a stepwise model of multiple regression analysis using estradiol and free and total testosterone as independent variables, estradiol was the only significant predictor of histomorphometric indices of bone formation and bone resorption in SHAM and ORX rats. These data show that androgen deficiency induces substantial loss of cancellous bone in the axial and appendicular skeleton of aged male rats and that this osteopenia is associated with a sustained increase in bone turnover. Thus, the skeletal effects of androgen withdrawal in aged male rats appear to resemble those induced by estrogen withdrawal in female rats. Furthermore, our study suggests that estradiol may act as a physiological suppressor of bone remodeling in aged male rats. (J Bone Miner Res 2000;15:1085-1098)
High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio
International journal of molecular sciences, 2014
The aim of this study was to evaluate effect of diosgenin (DG) on rats that had osteoporosis-like features induced by ovariectomy (OVX). Seventy-two six-month-old female Wistar rats were subjected to either ovariectomy (n = 60) or Sham operation (SHAM group, n = 12). Beginning at one week post-ovariectomy, the OVX rats were treated with vehicle (OVX group, n = 12), estradiol valerate (EV group, n = 12), or DG at three doses (DG-L, -M, -H group, n = 12, respectively). After a 12-week treatment, administration of EV or DG-H inhibited OVX-induced weight gain, and administration of EV or DG-H or DG-M had a significantly uterotrophic effect. Bone mineral density (BMD) and indices of bone histomorphometry of tibia were measured. Levels of protein and mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) in tibia were evaluated by immunohistochemistry and in situ hybridization. Our results show that DG at a high dose (DG-H) had a significa...
The androgen receptor has no direct antiresorptive actions in mouse osteoclasts
Androgen deficiency or androgen receptor knockout (ARKO) causes high-turnover osteopenia, but the target cells for this effect remain unclear. To examine whether AR in osteoclasts directly suppresses bone resorption, we crossed AR-floxed with cathepsin K-Cre mice. Osteoclast-specific ARKO (ocl-ARKO) mice showed no changes neither in osteoclast surface nor in bone microarchitecture nor in the response to orchidectomy and androgen replacement, indicating that the AR in osteoclasts is not critical for bone maintenance. In line with the lack of a bone phenotype, the levels of AR were very low in osteoclastenriched cultures derived from bone marrow (BM) and undetectable in osteoclasts generated from spleen precursors. Since tibiae of ubiquitous ARKO mice displayed increased osteoclast counts, the role of AR was further explored using cell cultures from these animals. Osteoclast generation and activity in vitro were similar between ARKO and wildtype control (WT) mice. In co-culture experiments, BM stromal cells (BMSCs) were essential for the suppressive action of AR on osteoclastogenesis and osteoclast activity. Stimulation with 1,25(OH)2 vitamin D3 increased Rankl and decreased Tnfsf11 (osteoprotegerin, Opg) gene expression in BMSCs more than in osteoblasts. This increase in the Rankl/Opg ratio following 1,25(OH)2D3 stimulation was lower, not higher, in ARKO mice. Runx2 expression in BMSCs was however higher in ARKO vs. WT, suggesting that ARKO mice may more readily commit osteoprogenitor cells to osteoblastogenesis. In conclusion, the AR does not seem to suppress bone resorption through direct actions in osteoclasts. BMSCs may however represent an alternative AR target in the BM milieu
2010
Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor B ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis. (Endocrine Reviews 29: 155-192, 2008) prostate cancer metastasis to bone J. RANKL and RANKL inhibition in animal models of multiple myeloma K. RANKL and RANKL inhibition in fracture and fracture repair IV. Role and Regulation of OPG/RANKL in the Human Skeleton A. Postmenopausal osteoporosis B. Men C. Glucocorticoid treatment D. Paget's disease of bone E. Rheumatoid arthritis V. Clinical Therapeutics Targeting the RANK/RANKL/OPG System A. Mechanism of action of denosumab B. Clinical studies of denosumab in postmenopausal women with osteoporosis
Journal of Bone and Mineral Research, 2009
RANKL is an essential mediator of bone resorption, and its activity is inhibited by osteoprotegerin (OPG). Transgenic (Tg) rats were engineered to continuously overexpress OPG to study the effects of continuous long-term RANKL inhibition on bone volume, density, and strength. Lumbar vertebrae, femurs, and blood were obtained from 1-yr-old female OPG-Tg rats (n = 32) and from age-matched wildtype (WT) controls (n = 23). OPG-Tg rats had significantly greater serum OPG (up to 260-fold) and significantly lower serum TRACP5b and osteocalcin compared with WT controls. Vertebral histomorphometry showed significant reductions in osteoclasts and bone turnover parameters in OPG-Tg rats versus WT controls, and these reductions were associated with significantly greater peak load in vertebrae tested through compression. No apparent differences in bone material properties were observed in OPG-Tg rat vertebrae, based on their unchanged intrinsic strength parameters and their normal linear relationship between vertebral bone mass and strength. Femurs from OPG-Tg rats were of normal length but showed mild osteopetrotic changes, including reduced periosteal perimeter (-6%) and an associated reduction in bending strength. Serum OPG levels in WT rats showed no correlations with any measured parameter of bone turnover, mass, or strength, whereas the supraphysiological serum OPG levels in OPG-Tg rats correlated negatively with bone turnover parameters and positively with vertebral bone mass and strength parameters. In summary, low bone turnover after 1 yr of OPG overexpression in rats was associated with increased vertebral bone mass and proportional increases in bone strength, with no evidence for deleterious effects on vertebral material properties.
Relationship between serum RANKL and RANKL in bone
Osteoporosis International, 2011
It is now well accepted that the molecule receptor activator of NFκB ligand (RANKL) and osteoprotegerin play key roles in regulating physiological and pathological bone turnover. There are a large number of published reports of circulating RANKL levels in both health and pathology. However, interpretation of these data has been elusive, and the relationship between circulating RANKL and RANKL levels in bone is still not clear. This review explores this subject, documenting the possible origins of circulating RANKL and suggesting additional information that is required before serum RANKL levels can provide useful diagnostic or research information.