Low bone mass and impaired fracture healing in mouse models of Trisomy21 (Down syndrome)

Sherman, Kirby M; Williams, Diarra K; Welsh, Casey A; Falck, Alyssa; Huggins, Shannon; Bokhari, Rihana; Gaddy, Dana; McKelvey, Kent D.; Dawson, Lindsay A.; Suva, Larry J.

doi:10.1016/j.bone.2022.116471

Cited by 8 publications

(3 citation statements)

References 66 publications

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“…There are many DS mouse models in which bone deficits have been characterized, including Ts65Dn, Dp1Tyb, Dp1Rhr, and Dp(16)1Yey (Blazek et al, 2011, Thomas et al, 2020, Sherman et al, 2022, Sloan et al, 2023). Ts65Dn mice are the most well characterized DS mouse model and appear to effectively model femoral DS-associated skeletal deficits, but skeletal studies in female mice have been limited because of the need to utilize these mice to generate additional mice.…”

Section: Discussionmentioning

confidence: 99%

Sex specific emergence of trisomicDyrk1a-related skeletal phenotypes in the development of a Down syndrome mouse model

LaCombe,

Sloan,

Thomas

et al. 2024

Preprint

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Skeletal insufficiency affects all individuals with Down syndrome (DS) or Trisomy 21 (Ts21) and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30 when there were persistent trabecular and cortical deficits and Dyrk1a was trending overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with Ts21.

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Section: Discussionmentioning

confidence: 99%

Sex specific emergence of trisomicDyrk1a-related skeletal phenotypes in the development of a Down syndrome mouse model

LaCombe,

Sloan,

Thomas

et al. 2024

Preprint

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“…[52,53] We therefore studied the function of osteoclasts derived from 2 DS mutant mouse lines, Dp16 and Ts65Dn, compared to their respective wild type (WT) controls as models of these skeletal abnormalities. [54] Use of multiple DS mutations is necessary to capture the full phenotypic variation of the DS mutation because the mouse equivalent of chromosome 21 is distributed in 3 mouse chromosomes. Ts65Dn possesses segmental trisomy representing 75% of homologous human gene while the Dp16 has a similar but more complete with the murine homologous human counterpart.…”

Section: Effect Of Peg-oacs On Osteoclast Differentiation In Ts65dn Micementioning

confidence: 99%

Oxidation of Hydrogen Sulfide to Polysulfide and Thiosulfate by a Carbon Nanozyme: Therapeutic Implications with an Emphasis on Down Syndrome

et al. 2023

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Hydrogen sulfide (H2S) is a noxious, potentially poisonous, but necessary gas produced from sulfur metabolism in humans. In Down Syndrome (DS), the production of H2S is elevated and associated with degraded mitochondrial function. Therefore, removing H2S from the body as a stable oxide could be an approach to reducing the deleterious effects of H2S in DS. In this report we describe the catalytic oxidation of hydrogen sulfide (H2S) to polysulfides (HS2+n−) and thiosulfate (S2O32−) by poly(ethylene glycol) hydrophilic carbon clusters (PEG‐HCCs) and poly(ethylene glycol) oxidized activated charcoal (PEG‐OACs), examples of oxidized carbon nanozymes (OCNs). We show that OCNs oxidize H2S to polysulfides and S2O32− in a dose‐dependent manner. The reaction is dependent on O2 and the presence of quinone groups on the OCNs. In DS donor lymphocytes we found that OCNs increased polysulfide production, proliferation, and afforded protection against additional toxic levels of H2S compared to untreated DS lymphocytes. Finally, in Dp16 and Ts65DN murine models of DS, we found that OCNs restored osteoclast differentiation. This new action suggests potential facile translation into the clinic for conditions involving excess H2S exemplified by DS.

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“…Currently, no statistical data or reported cases of humerus diaphysis nonunion of traumatic etiology in infants have been found. There are some articles suggesting an increased risk of fracture in patients with Down syndrome (DS) because of decreased bone density; however, the impairment of the consolidation process associated with DS is only described in animal models, which prevents definitive conclusions 7,8 . This report presents the first case of an atrophic and aseptic nonunion of the humerus diaphysis secondary to birth trauma in a 9-month-old infant girl with DS.…”

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confidence: 99%

Nonunion of Diaphyseal Humerus Fracture in an Infant

Beraún-Coronel

Cardenas-Escalante

Sinti-Paredes

et al. 2023

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Case: A 9-month-old infant girl with Down syndrome presented with an atrophic nonunion of the right humerus diaphysis secondary to birth trauma. Surgical intervention included open reduction and external fixation plus cadaveric cancellous bone allograft and platelet-rich plasma and then was changed to an external fixator in axial compression. At 16 months after surgery, bone healing was achieved. Conclusion:Nonunions in infants are rare, and their treatment is a challenge; an adequate vascular supply with good stabilization and reduction are keys to management. We believe that the improvement in reduction and stability under axial compression were the keys to achieve consolidation.Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C87).

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Low bone mass and impaired fracture healing in mouse models of Trisomy21 (Down syndrome)

Cited by 8 publications

References 66 publications

Sex specific emergence of trisomicDyrk1a-related skeletal phenotypes in the development of a Down syndrome mouse model

Sex specific emergence of trisomicDyrk1a-related skeletal phenotypes in the development of a Down syndrome mouse model

Oxidation of Hydrogen Sulfide to Polysulfide and Thiosulfate by a Carbon Nanozyme: Therapeutic Implications with an Emphasis on Down Syndrome

Nonunion of Diaphyseal Humerus Fracture in an Infant

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