Sarker Hassan, Hardy Eugenio, Haimour Ayman, Karim Mahmoud A, Scholl-Bürgi Sabine, Martignetti John A, Botto Lorenzo D, Fernandez-Patron Carlos
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Center of Molecular Immunology, Havana, Cuba.
Front Physiol. 2020 Sep 25;11:568718. doi: 10.3389/fphys.2020.568718. eCollection 2020.
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 ( ) 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 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 phenotypic traits of MMP-2 deficiency, we further studied mice. Among 32 cytokines measured in plasma of 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.
基质金属蛋白酶2（MMP - 2）缺乏会导致一种复杂综合征，其特征为多中心骨质溶解、结节病和关节病（MONA），以及心脏瓣膜缺陷、侏儒症和多毛症。MMP - 2缺陷小鼠是这种罕见的儿童多系统综合征的模型，但其表型仍未完全明确。在此，我们通过比较小鼠和人类体内细胞因子和趋化因子、可溶性细胞因子受体、血管生成因子、骨骼发育因子、载脂蛋白和激素的水平，扩展了对MMP - 2缺乏表型特征的认识。对一名8岁男性进行了初步筛查，该男性在基因中存在先前未报道的缺失突变c1294delC（Arg432fs），并被诊断为MONA。与未受影响的对照相比，在分析的81种血清生物分子中，11种上调（>4倍），2种下调（>4倍），68种保持不变。具体而言，该患者中嗜酸性粒细胞趋化因子、粒细胞 - 巨噬细胞集落刺激因子、巨噬细胞集落刺激因子、生长调节致癌基因α、巨噬细胞来源的趋化因子、白细胞介素 - 1β、白细胞介素 - 7、白细胞介素 - 12p40、巨噬细胞炎性蛋白 - 1α、巨噬细胞炎性蛋白 - 1β和γ干扰素诱导单核细胞趋化因子上调，而表皮生长因子（EGF）和促肾上腺皮质激素下调。对另外5名MMP - 2缺陷患者的后续分析证实了嗜酸性粒细胞趋化因子、白细胞介素 - 7、白细胞介素 - 12p40和巨噬细胞炎性蛋白 - 1α的上调以及EGF的下调。为了确定这些改变是否为MMP - 2缺乏的表型特征，我们进一步研究了小鼠。在小鼠血浆中检测的32种细胞因子中，嗜酸性粒细胞趋化因子、白细胞介素 - 1β、巨噬细胞炎性蛋白 - 1α和γ干扰素诱导单核细胞趋化因子在MMP - 2缺陷小鼠以及患者中均普遍上调。此外，具有生物活性的皮质醇（一种加剧骨质疏松的因子）在MMP - 2缺陷小鼠和患者中也升高。在我们已确定的MMP - 2缺乏时失调的因子中，许多是破骨细胞生成相关的，可能导致MONA中的骨骼疾病。这些新的分子表型特征值得在未来旨在了解儿童MMP - 2缺乏引发的病理机制的研究中作为靶点。
