The role of midkine in skeletal remodelling

Liedert, Astrid; Schinke, Thorsten; Ignatius, Anita; Amling, Michael

doi:10.1111/bph.12412

Cited by 17 publications

(12 citation statements)

References 107 publications

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“…The administration of rMK and rPTN has been proposed in a number of CNS and peripheral injuries, rending already significant effects in preclinical models, particularly in the case of myocardial ischemia (Christman et al, 2005b; Fukui et al, 2008) and bone repair (Lamprou et al, 2014; Liedert et al, 2014). Gene therapy or stem cells overexpressing these genes have also been proposed as delivery systems of these cytokines in different animal models of peripheral and central disorders and have been reviewed elsewhere (Muramatsu, 2011; Herradon and Perez-Garcia, 2014; Kadomatsu et al, 2014).…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development

2019

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Inflammation is a common factor of pathologies such as obesity, type 2 diabetes or neurodegenerative diseases. Chronic inflammation is considered part of the pathogenic mechanisms of different disorders associated with aging. Interestingly, peripheral inflammation and the associated metabolic alterations not only facilitate insulin resistance and diabetes but also neurodegenerative disorders. Therefore, the identification of novel pathways, common to the development of these diseases, which modulate the immune response and signaling is key. It will provide highly relevant information to advance our knowledge of the multifactorial process of aging, and to establish new biomarkers and/or therapeutic targets to counteract the underlying chronic inflammatory processes. One novel pathway that regulates peripheral and central immune responses is triggered by the cytokines pleiotrophin (PTN) and midkine (MK), which bind its receptor, Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, and inactivate its phosphatase activity. In this review, we compile a growing body of knowledge suggesting that PTN and MK modulate the immune response and/or inflammation in different pathologies characterized by peripheral inflammation associated with insulin resistance, such as aging, and in central disorders characterized by overt neuroinflammation, such as neurodegenerative diseases and endotoxemia. Evidence strongly suggests that regulation of the PTN and MK signaling pathways may provide new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN and/or MK cerebral levels and neuroinflammation. Importantly, we discuss existing therapeutics, and others being developed, that modulate these signaling pathways, and their potential use in pathologies characterized by overt neuroinflammation.

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Section: Therapeutic Perspectivesmentioning

confidence: 99%

Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development

2019

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“…Midkine is expressed during bone formation and fracture repair. By demonstrating a striking difference between wild-type and midkine-deficient mice, Liedert et al propose that midkine is a negative regulator of bone formation and mechanically induced bone remodeling (Liedert et al, 2014).…”

Section: Linked Articlesmentioning

confidence: 99%

Midkine: an emerging target of drug development for treatment of multiple diseases

Muramatsu

Kadomatsu

2014

British J Pharmacology

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Midkine is a multifunctional factor and has anti‐apoptotic, migration‐promoting, angiogenic, anti‐microbial and other activities. Midkine ameliorates ischemic injury in the heart and brain, enhances oocyte maturation, and is involved in neurogenesis. On the other hand, midkine is an important factor in the etiology of various diseases, especially those with inflammatory backgrounds. Furthermore, midkine is overexpressed in most malignant tumors and plays roles in their invasive phenotypes as well as in their resistance to chemotherapeutics. Therefore, midkine itself is expected to be useful for the treatment of brain and heart diseases, while midkine inhibitors are promising for the treatment of malignant tumors, multiple sclerosis, restenosis, renal diseases, hypertension and osteoporosis. Blood levels of midkine are also expected to be helpful as disease markers, especially as cancer markers. Linked Articles This article is part of a themed section on Midkine. To view the other articles in this section visit

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“…Our own previous work provided evidence that oestrogen-deficiency may affect the inflammatory response to fracture. We found that after bone fracture, OVX-mice displayed increased serum levels of midkine (Mdk) [ 23 ], a pro-inflammatory cytokine and a negative regulator of bone remodelling [ 24 – 26 ]. Mdk is an oestrogen-responsive gene and its expression is known to be up-regulated in the absence of oestrogen [ 27 , 28 ] as well as during inflammatory diseases and tissue injury and regeneration [ 29 – 33 ].…”

Section: Introductionmentioning

confidence: 99%

The inflammatory phase of fracture healing is influenced by oestrogen status in mice

Haffner‐Luntzer¹,

Fischer²,

Prystaz³

et al. 2017

Eur J Med Res

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BackgroundFracture healing is known to be delayed in postmenopausal, osteoporotic females under oestrogen-deficient conditions. Confirming this, experimental studies demonstrated impaired callus formation in ovariectomised animals. Oestrogen-deficiency is known to affect the immune system and the inflammatory response during wound healing. Because a balanced immune response is required for proper bone healing, we were interested to ascertain whether the early immune response after facture is affected by oestrogen depletion.MethodsTo address the above question, female mice received either a bilateral ovariectomy (OVX) or were sham-operated, and femur osteotomy was performed 8 weeks after OVX/sham operation. The effects of OVX on the presence of immune cells and pro-inflammatory cytokines were evaluated by flow cytometry and immunohistochemistry of the fracture calli on days 1 and 3 after fracture.ResultsOne day after fracture, immune cell numbers and populations in the fracture haematoma did not differ between OVX- and sham-mice. However, on day 3 after fracture, OVX-mice displayed significantly greater numbers of neutrophils. Local expression of the oestrogen-responsive and pro-inflammatory cytokine midkine (Mdk) and interleukin-6 (IL-6) expression in the fracture callus were increased in OVX-mice on day 3 after fracture compared with sham-mice, indicating that both factors might be involved in the increased presence of neutrophils. Confirming this, Mdk-antibody treatment decreased the number of neutrophils in the fracture callus and reduced local IL-6 expression in OVX-mice.ConclusionsThese data indicate that oestrogen-deficiency influences the early inflammatory phase after fracture. This may contribute to delayed fracture healing after oestrogen depletion.

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The role of midkine in skeletal remodelling

Cited by 17 publications

References 107 publications

Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development

Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development

Midkine: an emerging target of drug development for treatment of multiple diseases

The inflammatory phase of fracture healing is influenced by oestrogen status in mice

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