Thursday, May 1, 2025
5/1/2025
Mechanisms of inflammatory osteoblastogenesis and bone formation - The integrity of the adult skeleton is maintained by balanced remodeling between osteoclast-mediated bone resorption and osteoblast/osteocyte-mediated bone formation. However, excessive bone loss but limited bone formation often occur in many chronic inflammatory settings, such as rheumatoid arthritis (RA) and periodontitis. In contrast to the extensive studies on osteoclastic bone resorption, the deregulated osteoblastogenesis and damaged bone formation, especially in inflammatory conditions, are much less understood. There are no known effective therapies to improve bone formation in RA currently. We recently identified constitutive type-I Interferon (IFN-I) response activity in osteoblasts, evidenced by the constitutive expression of type I IFN-stimulated/response genes (ISGs), which is a newly recognized cellular signature of osteoblasts. It is intriguing that osteoblasts, a non-typical immune cell type, present IFN-I response signature in the absence of infection. We found that the constitutive IFN-I response plays an inhibitory role in osteoblast differentiation and bone formation with genetic evidence, which underscores its biological significance in osteoblastogenesis and bone homeostasis. ISGs are usually the indicators and effectors of IFN-I pathway/response. Among the ISGs, we identified Eif2ak2 (encoding eukaryotic translation initiation factor 2- alpha kinase 2) as an important inhibitor of osteogenesis. Importantly, Eif2ak2 is a central regulator of IFN-I response in osteoblastic inhibition. Eif2ak2-/- mice exhibit significantly high bone mass with prominently increased osteoblastic bone formation in vivo. Our data including RNAseq results further reveal a novel pathway mediated by IFN-I-Eif2ak2-β-catenin in the regulation of osteoblastogenesis. Moreover, inflammatory cytokine TNFα significantly enhances the constitutive IFN-I response in osteoblasts, indicating a novel molecular mechanism by which TNFα restrains bone formation. We also found a drastic aging effect of the constitutive IFN-I response on bone mass. Based on our preliminary results, in this application, we will further 1) investigate the mechanisms by which the constitutive IFN-I response suppresses osteoblastogenesis; 2) investigate how the effects of constitutive IFN-I response in osteoblasts/osteocytes on bone homeostasis are influenced by aging in both males and females; and 3) investigate the functional importance of constitutive IFN-I response in osteoblasts/osteocytes in inflammatory arthritic animal models with osteogenic defects. Successful completion of this proposal will shift the currently established paradigm in immunology for IFN-I response to a new paradigm in bone with distinct function and mechanisms. Identification of previously unrecognized mechanisms in osteogenic inhibition will provide a rational framework for developing new therapeutic approaches to enhancing osteoblast/osteocyte-mediated bone formation/repair in skeletal diseases.
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