Lipocalin 2 Influences Bone and Muscle Phenotype in the MDX Mouse Model of Duchenne Muscular Dystrophy

Ponzetti, Marco; Ucci, Argia; Maurizi, Antonio; Giacchi, Luca; Teti, Anna; Rucci, Nadia

doi:10.3390/ijms23020958

Cited by 17 publications

(9 citation statements)

References 40 publications

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“…after 3 months of age). This is a likely consequence of the increased inflammation and dystrophic phenotype of the skeletal muscle and is consistent with previous reports in mdx mice ( Nakagaki et al, 2011 ; Novotny et al, 2011 ; Ponzetti et al, 2022 ; Rufo et al, 2011 ; Wada et al, 2019 ). Interestingly, the age-related loss of trabecular bone was attenuated in older C. mdx 62 mice and, although interesting, the underlying mechanism for this remains unclear and warrants further investigation.…”

Section: Discussionsupporting

confidence: 93%

The BALB/c.mdx62 mouse exhibits a dystrophic muscle pathology and is a model of Duchenne muscular dystrophy

Swiderski,

Chan,

Herold

et al. 2024

Disease Models &Amp; Mechanisms

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Duchenne muscular dystrophy (DMD) is a devastating monogenic skeletal muscle wasting disorder. While many pharmacological and genetic interventions have been reported in preclinical studies, few have progressed to clinical trials with meaningful benefit. Identifying therapeutic potential may be limited by availability of suitable preclinical mouse models. More rigorous testing across models with varied background strains and mutations may identify treatments for clinical success. Here we report the generation of a DMD mouse model, with a CRISPR-induced deletion within exon 62 of the Dmd gene, and the first generated in BALB/c mice. Analysis of mice at 3, 6, and 12 months of age confirmed loss of Dp427 protein expression and resultant dystrophic pathology in limb muscles and the diaphragm, with evidence of centrally nucleated fibers, increased inflammatory markers and fibrosis, progressive decline in muscle function, and compromised trabecular bone development. The C.mdx62 mouse is a novel model of DMD with associated variations in the immune response and muscle phenotype, compared with existing models. It represents an important addition to the preclinical model toolbox for developing therapeutic strategies.

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Section: Discussionsupporting

confidence: 93%

The BALB/c.mdx62 mouse exhibits a dystrophic muscle pathology and is a model of Duchenne muscular dystrophy

Swiderski,

Chan,

Herold

et al. 2024

Disease Models &Amp; Mechanisms

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“…Image reconstruction was carried out employing a modified Feldkamp algorithm using the Skyscan Nrecon software. Three-dimensional (3D) and two-dimensional (2D) morphometric parameters were calculated for the trabecular bone, 100 slides (6.7 μm thick) from the growth plate [ 27 ]. 3D parameters were based on analysis of a Marching Cubes-type model with a rendered surface [ 28 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

Pre-proenkephalin 1 is Downregulated Under Unloading and is Involved in Osteoblast Biology

Puri,

Dannenberg,

Ucci

et al. 2024

Calcif Tissue Int

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Pre-proenkephalin 1 (Penk1) is a pro-neuropeptide that belongs to the typical opioid peptide’s family, having analgesic properties. We previously found Penk1 to be the most downregulated gene in a whole gene profiling analysis performed in osteoblasts subjected to microgravity as a model of mechanical unloading. In this work, Penk1 downregulation was confirmed in the bones of two in vivo models of mechanical unloading: tail-suspended and botulinum toxin A (botox)-injected mice. Consistently, in the sera from healthy volunteers subjected to bed rest, we observed an inverse correlation between PENK1 and bed rest duration. These results prompted us to investigate a role for this factor in bone. Penk1 was highly expressed in mouse bone, but its global deletion failed to impact bone metabolism in vivo. Indeed, Penk1 knock out (Penk1−/−) mice did not show an overt bone phenotype compared to the WT littermates. Conversely, in vitro Penk1 gene expression progressively increased during osteoblast differentiation and its transient silencing in mature osteoblasts by siRNAs upregulated the transcription of the Sost1 gene encoding sclerostin, and decreased Wnt3a and Col1a1 mRNAs, suggesting an altered osteoblast activity due to an impairment of the Wnt pathway. In line with this, osteoblasts treated with the Penk1 encoded peptide, Met-enkephalin, showed an increase of Osx and Col1a1 mRNAs and enhanced nodule mineralization. Interestingly, primary osteoblasts isolated from Penk1−/− mice showed lower metabolic activity, ALP activity, and nodule mineralization, as well as a lower number of CFU-F compared to osteoblasts isolated from WT mice, suggesting that, unlike the transient inhibition, the chronic Penk1 deletion affects both osteoblast differentiation and activity. Taken together, these results highlight a role for Penk1 in the regulation of the response of the bone to mechanical unloading, potentially acting on osteoblast differentiation and activity in a cell-autonomous manner.

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“…Excess LCN2 in mice reduces osteogenesis and increases osteoclastogenesis [123], whereas absence of Lcn2 leads to mild osteopenia, because of reduced bone formation [124]. In contrast, deletion of Lcn2 in experimental models of disuse-induced bone loss, such as Duchenne muscular dystrophy, leads to reductions in bone resorption and increases bone mass [125 ▪ ]. In a randomized control trial, circulating LCN2 levels predicted future risk of osteoporotic fractures requiring hospitalization [126].…”

Section: Lipocalin-2: a New Marker Of Disordered Bone And Mineral Met...mentioning

confidence: 99%

Lipocalin-2: a novel link between the injured kidney and the bone

Courbon

David

2022

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewFibroblast growth factor 23 (FGF23) excess is associated with left ventricular hypertrophy (LVH) and early mortality in patients with chronic kidney disease (CKD) and in animal models. Elevated Lipocalin-2 (LCN2), produced by the injured kidneys, contributes to CKD progression and might aggravate cardiovascular outcomes. The current review aims to highlight the role of LCN2 in CKD, particularly its interactions with FGF23. Recent findingsInflammation, disordered iron homeostasis and altered metabolic activity are common complications of CKD, and are associated with elevated levels of kidney-produced LCN2 and bone-secreted FGF23. A recent study shows that elevated LCN2 increases FGF23 production, and contributes to cardiac injury in patients and animals with CKD, whereas LCN2 reduction in mice with CKD reduces FGF23, improves cardiovascular outcomes and prolongs lifespan.

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Lipocalin 2 Influences Bone and Muscle Phenotype in the MDX Mouse Model of Duchenne Muscular Dystrophy

Cited by 17 publications

References 40 publications

The BALB/c.mdx62 mouse exhibits a dystrophic muscle pathology and is a model of Duchenne muscular dystrophy

The BALB/c.mdx62 mouse exhibits a dystrophic muscle pathology and is a model of Duchenne muscular dystrophy

Pre-proenkephalin 1 is Downregulated Under Unloading and is Involved in Osteoblast Biology

Lipocalin-2: a novel link between the injured kidney and the bone

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