DKK-1 a potential biomarker and therapeutic target in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a rare hereditary bone disorder with an estimated incidence of about 1 in 10,000 to 1 in 20,000 (1). It is characterized by low bone mass, increased bone fragility and recurrent fractures. The condition results from mutations that disrupt the synthesis and post-translational modification of type I collagen. Recent research indicates that the severity of OI phenotypes is influenced not only by abnormalities in type I collagen metabolism but also by alterations in osteoblast function (2), although the underlying mechanisms remain unclear. So far, none of the current available treatments have shown an overall efficacy in treating OI, thus demonstrating the unmet clinical need for managing OI (3). A recent study in mice has shown that  DKK1-antisense treatment can improve bone mechanical strength, restore the expression of osteogenic genes, stimulate osteogenesis, and suppress osteoclastogenesis in OI mice (3).

 

The Wnt/β-catenin pathways plays a key role in the regulation of osteogenesis. Dickkopf-1 (DKK-1) is a direct inhibitor of Wnt/β-catenin signaling by binding with high affinity to LRP5/LRP6 and Kremen proteins, inhibiting osteoblast function and bone formation. It is a soluble protein secreted in the bone microenvironment and can be detected in the circulation. In a recent study researchers measured DKK-1 concentrations in children with OI and examined its association with bone mineral density (BMD), fracture frequency, bone turnover markers, and the underlying genetic mutations of OI (4).

DKK-1 a potential biomarker and therapeutic target in Osteogenesis Imperfecta                                      

Key findings:

– concentrations were significantly higher in children with OI compared to healthy children

– DKK-1 is closely correlated to the skeletal phenotype of children with OI

– DKK-1 may become a novel biomarker and a potential therapeutic target of OI

 

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Correlation of serum DKK1 level with skeletal phenotype in children with osteogenesis imperfecta.  Wang Y et al., J Endocrinol Invest. 2024

Abstract

Purpose: We aim to detect serum DKK1 level of pediatric patients with OI and to analyze its relationship with the genotype and phenotype of OI patients.

Methods: A cohort of pediatric OI patients and age-matched healthy children were enrolled. Serum levels of DKK1 and bone turnover biomarkers were measured by enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by Dual-energy X-ray absorptiometry. Pathogenic mutations of OI were detected by next-generation sequencing and confirmed by Sanger sequencing.

Results: A total of 62 OI children with mean age of 9.50 (4.86, 12.00) years and 29 healthy children were included in this study. The serum DKK1 concentration in OI children was significantly higher than that in healthy children [5.20 (4.54, 6.32) and 4.08 (3.59, 4.92) ng/mL, P < 0.001]. The serum DKK1 concentration in OI children was negatively correlated with height (r = – 0.282), height Z score (r = – 0.292), ALP concentration (r = – 0.304), lumbar BMD (r = – 0.276), BMD Z score of the lumbar spine and femoral neck (r = – 0.32; r = – 0.27) (all P < 0.05). No significant difference in serum DKK1 concentration was found between OI patients with and without vertebral compression fractures. In patients with spinal deformity (22/62), serum DKK1 concentration was positively correlated with SDI (r = 0.480, P < 0.05). No significant correlation was observed between serum DKK1 concentration and the annual incidence of peripheral fractures, genotype and types of collagen changes in OI children.

Conclusion: The serum DKK1 level was not only significantly elevated in OI children, but also closely correlated to their skeletal phenotype, suggesting that DKK1 may become a new biomarker and a potential therapeutic target of OI.

Literature

1. Osteogenesis imperfecta: an update on clinical features and therapies. Marom R, Rabenhorst BM, Morello R. Eur J Endocrinol. 2020; 83(4):R95-R106. PMID: 32621590.
2. Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types. Jovanovic M, Guterman-Ram G, Marini JC. Endocr Rev. 2022; 43(1):61-90. PMID: 34007986.
3. Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease. Ko JY, Wang FS, Lian WS, Yang FS, Chen JW, Huang PH, Liao CY, Kuo SJ. Mol Med. 2024; 30(1):66. PMID: 38773377; PMCID.
4. Correlation of serum DKK1 level with skeletal phenotype in children with osteogenesis imperfecta. Wang Y, Hu J, Sun L, Zhou B, Lin X, Zhang Q, Wang O, Jiang Y, Xia W, Xing X, Li M. J Endocrinol Invest. 2024; 47(11):2785-2795. PMID: 38744806.

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