Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD)

Ng, Amy; Willett, Thomas L.; Alman, Benjamin A.; Grynpas, Marc D.

doi:10.1016/j.bone.2014.07.037

Cited by 9 publications

(9 citation statements)

References 52 publications

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“…49,50 The true prevalence of the adynamic bone condition in CKD is unknown because of a lack of consensus in its definition and diagnosis, with a reported prevalence range of 5% to 50% in dialysis patients. 51 In patients with advanced CKD Hutchison et al 52 and Hernandez et al 53 observed a prevalence of 28% and 30%, respectively, thus higher than Coen et al 47 Their patients also had lower serum intact PTH levels than those with other types of renal osteodystrophy, and they were receiving calcium carbonate treatment for the control of hyperphosphatemia. Adynamic bone disease in patients with CKD was mainly attributed by them and others to overtreatment of secondary hyperparathyroidism with PTH-lowering agents or relative or absolute hypoparathyroidism following surgical parathyroidectomy.…”

Section: Changes In Bone-related Serum Parameters and Ckd Progressionmentioning

confidence: 93%

Changing bone patterns with progression of chronic kidney disease

Drüeke¹,

Massy

2016

Kidney International

164

131

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It is commonly held that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy in patients with chronic kidney disease. Osteitis fibrosa is a high-turnover bone disease resulting mainly from secondary hyperparathyroidism, and mixed uremic osteodystrophy is in addition characterized by a mineralization defect most often attributed to vitamin D deficiency. However, there is ancient and more recent evidence that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients. This could be due to the initial predominance of bone turnover-inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/β-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4. The development of high-turnover bone disease would occur only later on, when serum PTH levels are able to overcome peripheral PTH resistance and the other inhibitory factors of bone formation. Whether FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease or participate only indirectly via regulating PTH secretion remains to be seen.

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Section: Changes In Bone-related Serum Parameters and Ckd Progressionmentioning

confidence: 93%

Changing bone patterns with progression of chronic kidney disease

Drüeke¹,

Massy

2016

Kidney International

164

131

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“…(12) Our previous study showed that at 4 months of age, the adynamic bone condition in our mouse altered the bone material and structural properties and shifted the bone to a more hypermineralized profile. (12) In the current study, we investigated the effects of increasing age on bone quality and how suppressed bone turnover further compounds the aging process on bone quality.…”

Section: Discussionmentioning

confidence: 64%

“…We assume this age-related decline in bone turnover applies to other skeletal sites, such as the tibia, as suggested by our previous study. (12) The strength of bone is determined by its material composition and structure. (24)(25)(26) Old adynamic animals had a higher BV/TV than old control animals, as well as a better-connected Fig.…”

Section: Discussionmentioning

confidence: 99%

“…(13,14) To create the adynamic bone condition, female Col2.3D-TK (DTK) mice were treated with ganciclovir (GCV) and pamidronate to mimic loss of bone turnover as described. (12) GCV depleted differentiated osteoblasts to prevent bone formation while pamidronate inhibited bone resorption by osteoclasts. Two age groups were used in this study: 4-month-old and 16-month-old animals representing young and old animals, respectively.…”

Section: Animalsmentioning

confidence: 99%

“…(6,11) Our laboratory previously established a novel mouse model of adynamic bone that directly targeted the actions of osteoblasts and osteoclasts. (12) In the current study, we used our mouse model of adynamic bone to explore how aging further compounds a state of low bone turnover because little is known about the effects of metabolic bone disease on bone toughness.…”

Section: Introductionmentioning

confidence: 99%

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Adynamic Bone Decreases Bone Toughness During Aging by Affecting Mineral and Matrix

Omelon

Variola

et al. 2015

Journal of Bone and Mineral Research

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Adynamic bone is the most frequent type of bone lesion in patients with chronic kidney disease; long-term use of antiresorptive therapy may also lead to the adynamic bone condition. The hallmark of adynamic bone is a loss of bone turnover, and a major clinical concern of adynamic bone is diminished bone quality and an increase in fracture risk. Our current study aims to investigate how bone quality changes with age in our previously established mouse model of adynamic bone. Young and old mice (4 months old and 16 months old, respectively) were used in this study. Col2.3Dtk (DTK) mice were treated with ganciclovir and pamidronate to create the adynamic bone condition. Bone quality was evaluated using established techniques including bone histomorphometry, microcomputed tomography, quantitative backscattered electron imaging, and biomechanical testing. Changes in mineral and matrix properties were examined by powder X-ray diffraction and Raman spectroscopy. Aging controls had a natural decline in bone formation and resorption with a corresponding deterioration in trabecular bone structure. Bone turnover was severely blunted at all ages in adynamic animals, which preserved trabecular bone loss normally associated with aging. However, the preservation of trabecular bone mass and structure in old adynamic mice did not rescue deterioration of bone mechanical properties. There was also a decrease in cortical bone toughness in old adynamic mice that was accompanied by a more mature collagen matrix and longer bone crystals. Little is known about the effects of metabolic bone disease on bone fracture resistance. We observed an age-related decrease in bone toughness that was worsened by the adynamic condition, and this decrease may be due to material level changes at the tissue level. Our mouse model may be useful in the investigation of the mechanisms involved in fractures occurring in elderly patients on antiresorptive therapy who have very low bone turnover.

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Loss of p62 impairs bone turnover and inhibits PTH‐induced osteogenesis

Agas

Amaroli

Lacava

et al. 2020

Journal Cellular Physiology

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The p62 (also named sequestosome1/SQSTM1) is multidomain and multifunctional protein associated with several physiological and pathological conditions. A number of studies evidenced an involvement of p62 on the disruptive bone scenarios due to its participation in the inflammatory/osteoclastogenic pathways. However, so far, information regarding the function of p62 in the fine-tuned processes underpinning the bone physiology are not well-defined and are sometime discordant. We, previously, demonstrated that the intramuscular administration of a plasmid coding for p62 was able to contrast bone loss in a mouse model of osteopenia. Here, in vitro findings showed that the p62 overexpression in murine osteoblasts precursors enhanced their maturation while the p62 depletion by a specific siRNA, decreased osteoblasts differentiation. Consistently, the activity of osteoblasts from p62 −/− mice was reduced compared with wild-type. Also, morphometric analyses of bone from p62 knockout mice revealed a pathological phenotype characterized by a lower turnover that could be explained by the poor Runx2 protein synthesis in absence of p62. Furthermore, we demonstrated that the parathyroid hormone (PTH) regulates p62 expression and that the osteogenic effects of this hormone were totally abrogated in osteoblasts from p62-deficient mice. Therefore, these findings, for the first time, highlight the important role of p62 both for the basal and for PTH-stimulated bone remodeling.

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Development, validation and characterization of a novel mouse model of Adynamic Bone Disease (ABD)

Cited by 9 publications

References 52 publications

Changing bone patterns with progression of chronic kidney disease

Changing bone patterns with progression of chronic kidney disease

Adynamic Bone Decreases Bone Toughness During Aging by Affecting Mineral and Matrix

Loss of p62 impairs bone turnover and inhibits PTH‐induced osteogenesis

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