Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Sato, Amy Y.; Cregor, Meloney; Delgado‐Calle, Jesús; Condon, Keith W.; Allen, Matthew R.; Peacock, Munro; Plotkin, Lilian I.; Bellido, Teresita

doi:10.1002/jbmr.2869

Cited by 109 publications

(123 citation statements)

References 77 publications

Supporting

Mentioning

112

Contrasting

Unclassified

Order By: Relevance

Section: Introductionmentioning

confidence: 74%

“…(10,13,14) In contrast, various studies that investigated the regulation of sclerostin have yielded inconsistent results and its role in GIO still remains unknown. The current study by Sato and colleagues (15) now provides compelling in vivo evidence that sclerostin expression is induced by pharmacological doses of GCs and, more importantly, that sclerostin plays a significant role in the pathogenesis of GIO as well, however in an unexpected fashion.Sato and colleagues (15) investigated the role of sclerostin in a mouse model of GIO that recapitulates many aspects of the human phenotype of GIO with trabecular thinning, an increase in bone resorption markers, osteocyte apoptosis, and a reduction in structural bone quality in female rodents. This underlines the suitability of the C57BL/6 mouse strain for studying GIO, which has been a matter of debate for several years.…”

mentioning

confidence: 74%

“…Sato and colleagues (15) investigated the role of sclerostin in a mouse model of GIO that recapitulates many aspects of the human phenotype of GIO with trabecular thinning, an increase in bone resorption markers, osteocyte apoptosis, and a reduction in structural bone quality in female rodents. This underlines the suitability of the C57BL/6 mouse strain for studying GIO, which has been a matter of debate for several years.…”

Section: Introductionmentioning

confidence: 99%

“…(10,16) In this mouse model, bone tissue levels of sclerostin were elevated in GC-treated mice, which is in line with previous data from Swiss-Webster mice. (6,15) Serum sclerostin levels were also increased after 12 months of high-dose GC therapy (7.5 mg/day) in a small study with 25 patients and correlated positively with both the GC dose and the lumbar bone mineral density.(17) In contrast, short-term exposure of 96 hours to exogenous GCs (range, 10 to 50 mg/day) or endogenous GC overproduction decreased serum levels of sclerostin. (18,19) Currently, the reasons for the inconsistent results remain unclear, but the heterogeneity of the underlying diseases of patients requiring GC therapy and the modulation of sclerostin by inflammatory cytokines and hormones (eg, PTH, vitamin D) may contribute to the varying results.…”

mentioning

confidence: 99%

“…To that end, the current study exposed sclerostin knockout mice to the model of chronic high-dose GC treatment. (15) …”

mentioning

confidence: 99%

See 4 more Smart Citations

Sclerostin Blockade—A Dual Mode of Action After All?

Baschant¹,

Henneicke

Hofbauer

et al. 2016

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

IntroductionG lucocorticoids (GCs) are frequently used to treat inflammatory diseases. However, GC excess, either due to long-term GC therapy or endogenous overproduction, often causes rapid bone loss. GC-induced osteoporosis (GIO) is the most common form of secondary osteoporosis with a predominant risk of vertebral fractures. Oral administration of as little as 2.5 mg prednisolone per day for more than 3 months already leads to a 1.5-fold increase in fracture risk, whereas the relative risk rises up to fivefold for daily doses of 7.5 mg per day or greater.(1)The molecular mechanisms underlying the deleterious effects of GC in bone are complex and incompletely understood. In principle, the pathogenesis of GIO occurs in two phases, an early rapid phase with bone loss due to transient excess bone resorption followed by a more sustained phase of suppressed bone formation.(2) Studies of direct effects of GC excess on osteoclasts have revealed inconsistent results, but overall suggest that GCs increase osteoclast formation and longevity.(3) Moreover, GCs indirectly enhance osteoclastogenesis by increasing receptor activator of NF-kB ligand (RANKL) and suppressing osteoprotegerin (OPG) expression in osteogenic cells. (4,5) Mouse studies have confirmed the importance of osteoclast activation in GIO because inhibiting osteoclasts using bisphosphonates or the RANKL antibody denosumab prevent bone loss. (4,6) Besides the increased bone resorption, the well-established hallmark of GIO at the cell biological level is the decrease of bone formation. Histomorphometric studies and serum analyses of patients revealed a reduced bone formation rate with an associated decrease in osteoid thickness, reduced mineral apposition rate, and decreased osteoblast activity.(7) Numerous studies over the last decade identified osteoblasts and osteocytes as the major target cells of GCs within the skeleton.(8-11) Pharmacological doses of GCs inhibit osteoblast differentiation and proliferation, increase osteoblast apoptosis, suppress pro-osteogenic gene expression, and enhance osteocyte autophagy and apoptosis. (12) Thus, the current cellular concept places impaired osteoblasts and osteocytes at the center of pathogenesis of GIO.The suppression of Wnt signaling in osteoblasts is one of the most critical mechanisms of GC-induced suppression of osteoblast function. In particular, the Wnt inhibitors dickkopf-1 (DKK-1) and sclerostin have been intensively investigated. Of those, DKK-1 expression is consistently upregulated by GCs, and knockdown studies in vivo confirmed its critical role in the pathogenesis of GIO. (10,13,14) In contrast, various studies that investigated the regulation of sclerostin have yielded inconsistent results and its role in GIO still remains unknown. The current study by Sato and colleagues (15) now provides compelling in vivo evidence that sclerostin expression is induced by pharmacological doses of GCs and, more importantly, that sclerostin plays a significant role in the pathogenesis of GIO as well, however in an une...

show abstract

Section: Introductionmentioning

confidence: 74%

mentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

“…To that end, the current study exposed sclerostin knockout mice to the model of chronic high-dose GC treatment. (15) …”

mentioning

confidence: 99%

See 3 more Smart Citations

Sclerostin Blockade—A Dual Mode of Action After All?

Baschant¹,

Henneicke

Hofbauer

et al. 2016

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

The CRH‐Transgenic Cushingoid Mouse Is a Model of Glucocorticoid‐Induced Osteoporosis

et al. 2017

View full text Add to dashboard Cite

Glucocorticoids (GCs) have unparalleled anti‐inflammatory and immunosuppressive properties, which accounts for their widespread prescription and use. Unfortunately, a limitation to GC therapy is a wide range of negative side effects including Cushing's syndrome, a disease characterized by metabolic abnormalities including muscle wasting and osteoporosis. GC‐induced osteoporosis occurs in 30% to 50% of patients on GC therapy and thus, represents an important area of study. Herein, we characterize the molecular and physiologic effects of GC‐induced osteoporosis using the Cushing's mouse model, the corticotropin releasing hormone (CRH) transgenic mouse (CRH‐Tg). The humeri, femurs, and tibias from wild‐type (WT) and CRH‐Tg male mice, aged 13 to 14 weeks old were subjected to multiple bone tests including, micro–computed tomography (μCT), static and dynamic histomorphometry, strength testing, and gene expression analyses. The CRH‐Tg mice had a 38% decrease in cortical bone area, a 35% decrease in cortical thickness, a 16% decrease in trabecular thickness, a sixfold increase in bone adiposity, a 27% reduction in osteoid width, a 75% increase in bone‐resorbing osteoclast number/bone surface, a 34% decrease in bone formation rate, and a 40% decrease in bone strength compared to WT mice. At the gene expression level, CRH‐Tg bone showed significantly increased osteoclast markers and decreased osteoblast markers, whereas CRH‐Tg muscle had increased muscle atrophy gene markers compared to WT mice. Overall, the CRH‐Tg mouse model aged to 14 weeks recapitulated many features of osteoporosis in Cushing's syndrome and thus, represents a useful model to study GC‐induced osteoporosis and interventions that target the effects of GCs on the skeleton. © 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

show abstract

Cx43 Overexpression in Osteocytes Prevents Osteocyte Apoptosis and Preserves Cortical Bone Quality in Aging Mice

et al. 2018

Self Cite

View full text Add to dashboard Cite

Young, skeletally mature mice lacking Cx43 in osteocytes exhibit increased osteocyte apoptosis and decreased bone strength, resembling the phenotype of old mice. Further, the expression of Cx43 in bone decreases with age, suggesting a contribution of reduced Cx43 levels to the age-related changes in the skeleton. We report herein that Cx43 overexpression in osteocytes achieved by using the DMP1-8kb promoter (Cx43OT mice) attenuates the skeletal cortical, but not trabecular bone phenotype of aged, 14-month-old mice. The percentage of Cx43-expressing osteocytes was higher in Cx43OT mice, whereas the percentage of Cx43 positive osteoblasts remained similar to wild type (WT) littermate control mice. The percentage of apoptotic osteocytes and osteoblasts was increased in aged WT mice compared to skeletally mature, 6-month-old WT mice, and the percentage of apoptotic osteocytes, but not osteoblasts, was decreased in age-matched Cx43OT mice. Aged WT mice exhibited decreased bone formation and increased bone resorption as quantified by histomorphometric analysis and circulating markers, compared to skeletally mature mice. Further, aged WT mice exhibited the expected decrease in bone biomechanical structural and material properties compared to young mice. Cx43 overexpression prevented the increase in osteoclasts and decrease in bone formation on the endocortical surfaces, and the changes in circulating markers in the aged mice. Moreover, the ability of bone to resist damage was preserved in aged Cx43OT mice both at the structural and material level. All together, these findings suggest that increased Cx43 expression in osteocytes ameliorates age-induced cortical bone changes by preserving osteocyte viability and maintaining bone formation, leading to improved bone strength.

show abstract

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Cited by 109 publications

References 77 publications

Sclerostin Blockade—A Dual Mode of Action After All?

Sclerostin Blockade—A Dual Mode of Action After All?

The CRH‐Transgenic Cushingoid Mouse Is a Model of Glucocorticoid‐Induced Osteoporosis

Cx43 Overexpression in Osteocytes Prevents Osteocyte Apoptosis and Preserves Cortical Bone Quality in Aging Mice

Contact Info

Product

Resources

About