Osteoporosis is a common bone metabolic disorder characterized by reduced bone mass and deterioration of bone microarchitecture, and frequently observed in older adults, postmenopausal women, and individuals with chronic inflammatory conditions. Previous studies have shown that growth factors and other secretory proteins affect bone remodeling, resulting in osteoporosis.
A recent study in Genes & Diseases by researchers from The Second Affiliated Hospital of Soochow University, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), and the Medical College of Soochow University, investigated the mechanistic role of midkine (MDK), a heparin-binding growth factor implicated in bone remodeling and inflammatory regulation, elucidating how its inhibition exerts protective effects against bone deterioration.
By using a multidisciplinary approach involving clinical data derived from postmenopausal women, bioinformatics, in vitro cellular assays, and in vivo animal models, the authors demonstrate that elevated MDK expression is associated with impaired osteogenic differentiation and heightened inflammatory responses, both of which contribute to the progression of bone loss under pathological conditions. Clinical data identified a robust negative correlation between serum MDK concentrations and bone mineral density (BMD) at critical anatomical sites, including the lumbar spine and hip, while trabecular bone loss in an ovariectomized (OVX) mouse model corroborated the clinical findings.
In vivo experiments using iMDK, a small-molecule MDK inhibitor, revealed that intraperitoneal injections of iMDK effectively countered estrogen deficiency-induced bone loss by enhancing bone formation and suppressing inflammatory signals, evident from improved key trabecular bone parameters and increased levels of osteocalcin (OCN), thereby highlighting the therapeutic potential of targeting MDK.
Additionally, in vitro assays with recombinant MDK protein showed that MDK inhibits osteogenic differentiation in a dose-dependent manner, suppressing alkaline phosphatase (ALP) activity and the formation of mineralized nodules. Mechanistically, MDK exerts inhibitory effects on osteoblast differentiation by suppressing the PI3K/Akt signaling pathway, a critical regulator of cell survival, proliferation, and osteogenic commitment. Attenuation of PI3K/Akt signaling by MDK leads to reduced activation of downstream transcription factors essential for osteoblast maturation, thereby impairing mineralization and bone formation. Conversely, inhibition of MDK restores PI3K/Akt pathway activity, promoting osteogenic gene expression and enhancing the differentiation capacity of mesenchymal progenitor cells.
In parallel, MDK was found to potentiate inflammatory responses via activation of the NF-κB signaling pathway, a central mediator of immune and inflammatory gene expression. Elevated MDK levels facilitate NF-κB nuclear translocation and transcriptional activity, resulting in the upregulation of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. This inflammatory milieu not only exacerbates local tissue damage but also promotes osteoclastogenesis, thereby accelerating bone resorption. Importantly, pharmacological or genetic inhibition of MDK significantly suppresses NF-κB activation, leading to decreased cytokine production and attenuation of inflammation-driven bone degradation. These findings position MDK as a critical upstream regulator linking inflammatory signaling to skeletal pathology.
Collectively, the findings provide a comprehensive mechanistic framework in which MDK drives bone loss through coordinated inhibition of PI3K/Akt-mediated osteogenesis and activation of NF-κB-dependent inflammatory pathways. By elucidating these signaling axes, the study not only advances the understanding of the molecular underpinnings of bone metabolism but also identifies MDK as a viable and strategically advantageous target for the development of therapies aimed at restoring skeletal integrity in inflammatory bone disorders.
Reference
Title of the original paper: Targeting MDK alleviates bone loss via dual regulation of osteogenic differentiation and inflammatory cytokine expression
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101931
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