Promethazine Hydrochloride Inhibits Ectopic Fat Cell Formation in Skeletal Muscle

Kasai, Takehiro; Nakatani, Masashi; Ishiguro, Naoki; Ohno, Kinji; Yamamoto, Naoki; Morita, Mitsuhiro; Yamada, Harumoto; Tsuchida, Kunihiro; Uezumi, Akiyoshi

doi:10.1016/j.ajpath.2017.08.008

Cited by 11 publications

(13 citation statements)

References 21 publications

(28 reference statements)

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“…Further, the use of tyrosine kinase inhibitors prevents excessive FAP proliferation in DMD mouse model 19,20 , has toxicity associated with their long-term use required for LGMD2B. Our identification of inhibiting adipogenesis in dysferinopathic muscle by targeting FAPs by MMP-14 inhibitors (batimastat) also opens avenues for the use of other candidate drugs like promethazine, which also inhibits FAP adipogenesis 63 . In principle, the direct manipulation of PDGFRα splicing by morpholinos may also be beneficial by preventing FAP proliferation 64 .…”

Section: Discussionmentioning

confidence: 93%

Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B

et al. 2019

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Muscle loss due to fibrotic or adipogenic replacement of myofibers is common in muscle diseases and muscle-resident fibro/adipogenic precursors (FAPs) are implicated in this process. While FAP-mediated muscle fibrosis is widely studied in muscle diseases, the role of FAPs in adipogenic muscle loss is not well understood. Adipogenic muscle loss is a feature of limb girdle muscular dystrophy 2B (LGMD2B) – a disease caused by mutations in dysferlin. Here we show that FAPs cause the adipogenic loss of dysferlin deficient muscle. Progressive accumulation of Annexin A2 (AnxA2) in the myofiber matrix causes FAP differentiation into adipocytes. Lack of AnxA2 prevents FAP adipogenesis, protecting against adipogenic loss of dysferlinopathic muscle while exogenous AnxA2 enhances muscle loss. Pharmacological inhibition of FAP adipogenesis arrests adipogenic replacement and degeneration of dysferlin-deficient muscle. These results demonstrate the pathogenic role of FAPs in LGMD2B and establish these cells as therapeutic targets to ameliorate muscle loss in patients.

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Section: Discussionmentioning

confidence: 93%

Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B

et al. 2019

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“…In humans, cell-surface markers like PDGFRα, CD201, CD166, CD105, CD90, CD73, and CD15 identify skeletal muscle FAPs (Table 2 ) [ 16 , 51 , 53 , 54 , 64 , 71 , 72 ]. Remarkably, the expression of SCA-1 defines a particular cluster of stromal cells within the murine FAP population with different potency and properties in vivo and in vitro, both in the skeletal muscle and heart [ 66 , 73 ].…”

Section: The Developmental Ontology Of Muscle-resident Mesenchymal Progenitorsmentioning

confidence: 99%

“… Reduced? Not evaluated Reduced Reduced [ 154 ] Promethazine hydrochloride H1 histamine receptor Not affected Not affected Not affected Not evaluated Reduced [ 72 ] SB525334/SB431542 TGFBR kinase activity inhibitor Reduced Reduced Induced after long treatment Reduced Not evaluated [ 147 ] [ 11 , 12 ] TKIs (imatinib, nilotinib, crenolanib, sorafenib, and masitinib) Abl, PDGFRs, Kit, DDRs, p38 Reduced Reduced Induced Reduced Reduced and/or Induced [ 59 ]; [ 155 ]; [ 11 , 12 ]; b [ 16 ]; [ 146 ]; a HDACs-mediated effects on FAP fate are seen only in young mdx but not aged mdx mice b [ 16 ] reported that imatinib enhances the amount of perilipin+ FAP-derived adipocytes in vitro …”

Section: Multipotency Of Muscle-resident Pdgfrα+ Fibro-adipogenic Progenitorsmentioning

confidence: 99%

“…Hence, altered synthesis of NO, a typical finding in DMD, could contribute to enhanced fat deposition. On the search for adipogenic inhibitors, Uezumi and colleagues found that promethazine hydrochloride inhibits, through binding to the H1 histamine receptor, the in vitro and in vivo formation of ectopic adipocytes derived from PDGFRα+ lineage cells in the muscle [ 72 ] (Table 3 ). Promethazine hydrochloride is a first-generation antagonist of the H1 histamine receptor, and therefore, this family of drugs emerge as attractive novel therapeutics against ectopic fat formation in muscle pathologies.…”

Section: Multipotency Of Muscle-resident Pdgfrα+ Fibro-adipogenic Progenitorsmentioning

confidence: 99%

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Origins, potency, and heterogeneity of skeletal muscle fibro-adipogenic progenitors—time for new definitions

2021

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Striated muscle is a highly plastic and regenerative organ that regulates body movement, temperature, and metabolism—all the functions needed for an individual’s health and well-being. The muscle connective tissue’s main components are the extracellular matrix and its resident stromal cells, which continuously reshape it in embryonic development, homeostasis, and regeneration. Fibro-adipogenic progenitors are enigmatic and transformative muscle-resident interstitial cells with mesenchymal stem/stromal cell properties. They act as cellular sentinels and physiological hubs for adult muscle homeostasis and regeneration by shaping the microenvironment by secreting a complex cocktail of extracellular matrix components, diffusible cytokines, ligands, and immune-modulatory factors. Fibro-adipogenic progenitors are the lineage precursors of specialized cells, including activated fibroblasts, adipocytes, and osteogenic cells after injury. Here, we discuss current research gaps, potential druggable developments, and outstanding questions about fibro-adipogenic progenitor origins, potency, and heterogeneity. Finally, we took advantage of recent advances in single-cell technologies combined with lineage tracing to unify the diversity of stromal fibro-adipogenic progenitors. Thus, this compelling review provides new cellular and molecular insights in comprehending the origins, definitions, markers, fate, and plasticity of murine and human fibro-adipogenic progenitors in muscle development, homeostasis, regeneration, and repair.

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“…In our previous study, we established isolation and culturing method of platelet‐derived growth factor receptor α positive (PDGFRα+) cells in mouse and human skeletal muscles, which are responsible for fatty degeneration, fibrosis, and ossification in skeletal muscle 10–12 . Furthermore, we reported PDGFRα+ cells as the authentic origin of HO in skeletal muscle 13,14 .…”

Section: Introductionmentioning

confidence: 99%

Desloratadine inhibits heterotopic ossification by suppression of BMP2‐Smad1/5/8 signaling

Kusano

Nakatani

Ishiguro

et al. 2020

Journal Orthopaedic Research

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Heterotopic ossification (HO) is a pathological condition in which ectopic bone forms within soft tissues such as skeletal muscle. Human platelet‐derived growth factor receptor α positive (PDGFRα+) cells, which were proved to be the original cells of HO were incubated in osteogenic differentiation medium with Food and Drug Administration‐approved compounds. Alkaline phosphatase activity was measured as a screening to inhibit osteogenic differentiation. For the compounds which inhibited osteogenic differentiation of PDGFRα+ cells, we examined dose dependency of its effect using alizarin red S staining and its cell toxicity using WST‐8. In addition, regulation of bone morphogenetic proteins (BMP)‐Smad signaling which is the major signal of osteogenic differentiation was investigated by Western blotting to elucidate the mechanism of osteogenesis inhibitory effect by the compound. In vivo experiment, complete transverse incision of Achilles tendons in mice was made and mice were fed the compound by mixing with drinking water after operation. Ten weeks after operation, we assessed and quantified HO by micro‐computed tomography scan. Intriguingly, we discovered desloratadine inhibited osteogenic differentiation of PDGFRα+ cells using the drug repositioning method. Desloratadine inhibited osteogenic differentiation of the cells dose dependently without cell toxicity. Desloratadine suppressed phosphorylation of Smad1/5/8 induced by BMP2 in PDGFRα+ cells. In Achilles tenotomy mice model, desloratadine treatment significantly inhibited ectopic bone formation compared with control. In conclusion, we discovered desloratadine inhibited osteogenic differentiation using human PDGFRα+ cells and proved its efficacy using Achilles tenotomy ectopic bone formation model in vivo. Our study paved the way to inhibit HO in early clinical use because of its guaranteed safety.

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Promethazine Hydrochloride Inhibits Ectopic Fat Cell Formation in Skeletal Muscle

Cited by 11 publications

References 21 publications

Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B

Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B

Origins, potency, and heterogeneity of skeletal muscle fibro-adipogenic progenitors—time for new definitions

Desloratadine inhibits heterotopic ossification by suppression of BMP2‐Smad1/5/8 signaling

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