Comparative Serum Analyses Identify Cytokines and Hormones Commonly Dysregulated as Well as Implicated in Promoting Osteolysis in MMP-2-Deficient Mice and Children

Hassan Sarker; Eugenio Hardy; Ayman Haimour; Mahmoud A Karim; Sabine Scholl-Bürgi; John A Martignetti; Lorenzo D Botto; Carlos Fernandez-Patron

doi:10.3389/fphys.2020.568718

Comparative Serum Analyses Identify Cytokines and Hormones Commonly Dysregulated as Well as Implicated in Promoting Osteolysis in MMP-2-Deficient Mice and Children

Front Physiol. 2020 Sep 25:11:568718. doi: 10.3389/fphys.2020.568718. eCollection 2020.

Authors

Hassan Sarker¹, Eugenio Hardy², Ayman Haimour¹, Mahmoud A Karim³, Sabine Scholl-Bürgi⁴, John A Martignetti^{5

6}, Lorenzo D Botto⁷, Carlos Fernandez-Patron¹

Affiliations

¹ Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
² Center of Molecular Immunology, Havana, Cuba.
³ Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
⁴ Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
⁶ Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT, United States.
⁷ Department of Pediatrics, Division of Medical Genetics and Pediatrics, The University of Utah, Salt Lake City, UT, United States.

Abstract

Deficiency of matrix metalloproteinase 2 (MMP-2) causes a complex syndrome characterized by multicentric osteolysis, nodulosis, and arthropathy (MONA) as well as cardiac valve defects, dwarfism and hirsutism. MMP-2 deficient (Mmp2 ^-/-) mice are a model for this rare multisystem pediatric syndrome but their phenotype remains incompletely characterized. Here, we extend the phenotypic characterization of MMP-2 deficiency by comparing the levels of cytokines and chemokines, soluble cytokine receptors, angiogenesis factors, bone development factors, apolipoproteins and hormones in mice and humans. Initial screening was performed on an 8-year-old male presenting a previously unreported deletion mutation c1294delC (Arg432fs) in the MMP2 gene and diagnosed with MONA. Of eighty-one serum biomolecules analyzed, eleven were upregulated (>4-fold), two were downregulated (>4-fold) and sixty-eight remained unchanged, compared to unaffected controls. Specifically, Eotaxin, GM-CSF, M-CSF, GRO-α, MDC, IL-1β, IL-7, IL-12p40, MIP-1α, MIP-1β, and MIG were upregulated and epidermal growth factor (EGF) and ACTH were downregulated in this patient. Subsequent analysis of five additional MMP-2 deficient patients confirmed the upregulation in Eotaxin, IL-7, IL-12p40, and MIP-1α, and the downregulation in EGF. To establish whether these alterations are bona fide phenotypic traits of MMP-2 deficiency, we further studied Mmp2 ^-/- mice. Among 32 cytokines measured in plasma of Mmp2 ^-/- mice, the cytokines Eotaxin, IL-1β, MIP-1α, and MIG were commonly upregulated in mice as well as patients with MMP-2 deficiency. Moreover, bioactive cortisol (a factor that exacerbates osteoporosis) was also elevated in MMP-2 deficient mice and patients. Among the factors we have identified to be dysregulated in MMP-2 deficiency many are osteoclastogenic and could potentially contribute to bone disorder in MONA. These new molecular phenotypic traits merit being targeted in future research aimed at understanding the pathological mechanisms elicited by MMP-2 deficiency in children.

Keywords: cortisol; cytokines; matrix metalloproteinase; matrix metalloproteinase-2; multicentric osteolysis nodulosis and arthropathy.