Osteoprotegerin ameliorates sciatic nerve crush induced bone loss

Bateman, Ted A.; Dunstan, Colin R.; Ferguson, Virginia L.; Ayers, Reed; Simske, Steven J.

doi:10.1016/s0736-0266(00)00057-7

Cited by 17 publications

(13 citation statements)

References 27 publications

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“…There are several useful models of bone loss induced by ovariectomy (OVX) (18, 19), denervation (21), LPS administration (22) and tail-suspension (20) which however, require distinctive surgical skills, care and are also traumatic to animals. Alternatively, a high fat diet-induced obesity in mice is a simple and convenient method.…”

Section: Discussionmentioning

confidence: 99%

High fat diet-induced animal model of age-associated obesity and osteoporosis

Halade

Rahman

Williams

et al. 2010

The Journal of Nutritional Biochemistry

151

138

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Osteoporosis and obesity remain a major public health concern through its associated fragility and fractures. Several animal models for the study of osteoporotic bone loss, such as ovariectomy (OVX) and denervation, require unique surgical skills and expensive set up. The challenging aspect of these age-associated diseases is that no single animal model exactly mimics the progression of these human-specific chronic conditions. Accordingly, to develop a simple and novel model of post menopausal bone loss with obesity, we fed either a high fat diet containing 10% corn oil (CO) or standard rodent lab chow (LC) to 12 month old female C57Bl/6J mice for 6 months. As a result, CO fed mice exhibited increased body weight, total body fat mass (BFM), abdominal fat mass and reduced bone mineral density (BMD) in different skeletal sites measured by Dual Energy X-ray Absorptiometry (DXA). We also observed that decreased bone mineral density (BMD) with age in CO fed obese mice was accompanied by increased bone marrow adiposity, up-regulation of PPARγ, cathepsin k and increased pro-inflammatory cytokines (IL-6 and TNF-α) in bone marrow and splenocytes, when compared to that of LC fed mice. Therefore, this appears to be a simple, novel and convenient age-associated model of post menopausal bone loss, in conjunction with obesity, which can be used in pre-clinical drug discovery to screen new therapeutic drugs or dietary interventions for the treatment of obesity and osteoporosis in the human population.

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Section: Discussionmentioning

confidence: 99%

High fat diet-induced animal model of age-associated obesity and osteoporosis

Halade

Rahman

Williams

et al. 2010

The Journal of Nutritional Biochemistry

151

138

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“…Common rodent disuse models include tail suspension, sciatic neurectomy or crush, and spaceflight. OPG reduced cortical bone resorption and increased bone density in mouse nerve crush models (290,291). OPG also prevented decreases in BMD and bone strength in a rat sciatic neurectomy model.…”

Section: F Rankl and Rankl Inhibition In Disuse Osteopenia Modelsmentioning

confidence: 99%

Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease

2007

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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: 2008)

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“…In contrast, exogenous OPG prevents estrogen deficiency-associated bone loss in ovariectomized animals, and in all of the osteolytic and osteopenic pathologies in which it has been tested (Simonet et al, 1997;Horwood et al, 1999;Feige et al, 2000;Romas et al, 2000;Bateman et al, 2001;Haynes et al, 2001;Kotake et al, 2001).…”

mentioning

confidence: 99%

Osteoprotegerin (OPG) is localized to the Weibel‐Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor

Zannettino

Holding

Diamond

et al. 2005

Journal Cellular Physiology

142

148

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Recent studies demonstrate roles for osteoprotegerin (OPG) in both skeletal and extra-skeletal tissues. Although its role in preventing osteoclast (OC) formation and activity is well documented, emerging evidence suggests a role of OPG in endothelial cell survival and the prevention of arterial calcification. In this communication, we show that vascular endothelial cells in situ, and human umbilical vein endothelial cells (HUVEC) in vitro, express abundant OPG. In HUVEC, OPG co-localizes with P-selectin and von Willebrand factor (vWF), within the Weibel-Palade bodies (WPB). Treatment of HUVEC with the pro-inflammatory cytokines, tumor necrosis factor (TNF)-alpha and IL-1beta, resulted in mobilization from the WPBs and subsequent secretion of OPG protein into the culture supernatant. Furthermore, TNF-alpha treatment of HUVEC resulted in a sustained increase in OPG mRNA levels and protein secretion over the 24-h treatment period. Reciprocal immunoprecipitation experiments revealed that while not associated with P-Selectin, OPG is physically complexed with vWF both within the WPB and following secretion from endothelial cells. Interestingly, this association was also identified in human peripheral blood plasma. In addition to its interaction with vWF, we show that OPG also binds with high avidity to the vWF reductase, thrombospondin (TSP-1), raising the intriguing possibility that OPG may provide a link between TSP-1 and vWF. In summary, the intracellular localization of OPG in HUVEC, in association with vWF, together with its rapid and sustained secretory response to inflammatory stimuli, strongly support a modulatory role in vascular injury, inflammation and hemostasis.

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Osteoprotegerin ameliorates sciatic nerve crush induced bone loss

Cited by 17 publications

References 27 publications

High fat diet-induced animal model of age-associated obesity and osteoporosis

High fat diet-induced animal model of age-associated obesity and osteoporosis

Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease

Osteoprotegerin (OPG) is localized to the Weibel‐Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor

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