Ewanchuk Benjamin W, Arnold Corey R, Balce Dale R, Premnath Priyatha, Orsetti Tanis L, Warren Amy L, Olsen Alexandra, Krawetz Roman J, Yates Robin M
Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Sci Adv. 2021 Apr 23;7(17). doi: 10.1126/sciadv.abd3684. Print 2021 Apr.
The extracellular bone resorbing lacuna of the osteoclast shares many characteristics with the degradative lysosome of antigen-presenting cells. γ-Interferon-inducible lysosomal thiol reductase (GILT) enhances antigen processing within lysosomes through direct reduction of antigen disulfides and maintenance of cysteine protease activity. In this study, we found the osteoclastogenic cytokine RANKL drove expression of GILT in osteoclast precursors in a STAT1-dependent manner, resulting in high levels of GILT in mature osteoclasts, which could be further augmented by γ-interferon. GILT colocalized with the collagen-degrading cysteine protease, cathepsin K, suggesting a role for GILT inside the osteoclastic resorption lacuna. GILT-deficient osteoclasts had reduced bone-resorbing capacity, resulting in impaired bone turnover and an osteopetrotic phenotype in GILT-deficient mice. We demonstrated that GILT could directly reduce the noncollagenous bone matrix protein SPARC, and additionally, enhance collagen degradation by cathepsin K. Together, this work describes a previously unidentified, non-immunological role for GILT in osteoclast-mediated bone resorption.
破骨细胞的细胞外骨吸收腔隙与抗原呈递细胞的降解性溶酶体具有许多共同特征。γ-干扰素诱导的溶酶体硫醇还原酶（GILT）通过直接还原抗原二硫键和维持半胱氨酸蛋白酶活性来增强溶酶体内的抗原加工。在本研究中，我们发现破骨细胞生成细胞因子RANKL以STAT1依赖的方式驱动破骨细胞前体中GILT的表达，导致成熟破骨细胞中GILT水平升高，γ-干扰素可进一步增强其表达。GILT与降解胶原蛋白的半胱氨酸蛋白酶组织蛋白酶K共定位，提示GILT在破骨细胞吸收腔隙内发挥作用。GILT缺陷的破骨细胞骨吸收能力降低，导致GILT缺陷小鼠的骨转换受损和骨质石化表型。我们证明GILT可以直接还原非胶原蛋白骨基质蛋白SPARC，此外，还能增强组织蛋白酶K对胶原蛋白的降解。总之，这项工作描述了GILT在破骨细胞介导的骨吸收中以前未被识别的非免疫作用。
