20
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Activation of mTORC1 in subchondral bone preosteoblasts promotes osteoarthritis by stimulating bone sclerosis and secretion of CXCL12

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Increasing evidences show that aberrant subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). However, how subchondral bone formation is activated and the mechanism by which increased subchondral bone turnover promotes cartilage degeneration during OA remains unclear. Here, we show that the mechanistic target of rapamycin complex 1 (mTORC1) pathway is activated in subchondral bone preosteoblasts (Osterix+) from OA patients and mice. Constitutive activation of mTORC1 in preosteoblasts by deletion of the mTORC1 upstream inhibitor, tuberous sclerosis 1, induced aberrant subchondral bone formation, and sclerosis with little-to-no effects on articular cartilage integrity, but accelerated post-traumatic OA development in mice. In contrast, inhibition of mTORC1 in preosteoblasts by disruption of Raptor (mTORC1-specific component) reduced subchondral bone formation and cartilage degeneration, and attenuated post-traumatic OA in mice. Mechanistically, mTORC1 activation promoted preosteoblast expansion and Cxcl12 secretion, which induced subchondral bone remodeling and cartilage degeneration during OA. A Cxcl12-neutralizing antibody reduced cartilage degeneration and alleviated OA in mice. Altogether, these findings demonstrate that mTORC1 activation in subchondral preosteoblasts is not sufficient to induce OA, but can induce aberrant subchondral bone formation and secrete of Cxcl12 to accelerate disease progression following surgical destabilization of the joint. Pharmaceutical inhibition of the pathway presents a promising therapeutic approach for OA treatment.

          Arthritis: Activation of mTORC1 promotes osteoarthritis by stimulating bone sclerosis

          Mammalian target of rapamycin complex 1 (mTORC1) is a protein complex that controls protein synthesis, and activation of mTORC1 in subchondral preosteoblasts promotes arthritis by stimulating bone sclerosis (abnormal hardening) and secreting C-X-C motif chemokine 12 (CXCL12). Subchondral preosteoblasts are cells that differentiate into bone-forming cells below the cartilage in joints, and CXCL12 is a protein that regulates a wide range of cellular activities. A team headed by Daozhang Cai and Xiaochun Bai of The Third Affiliated Hospital of Southern Medical University, Guangzhou, China investigated mTORC1 activity in subchondral preosteoblasts from osteoarthritis patients and mice. The team found that mTORC1 activation of subchondral preosteoblasts promoted osteoarthritis by stimulating abnormal subchondral bone formation and secretion of CXCL12, promoting cartilage degeneration. The authors believe that pharmaceutical inhibition of that pathway offers a promising approach in treating osteoarthritis.

          Related collections

          Most cited references47

          • Record: found
          • Abstract: found
          • Article: not found

          Osteoarthritis cartilage histopathology: grading and staging.

          Current osteoarthritis (OA) histopathology assessment methods have difficulties in their utility for early disease, as well as their reproducibility and validity. Our objective was to devise a more useful method to assess OA histopathology that would have wide application for clinical and experimental OA assessment and would become recognized as the standard method. An OARSI Working Group deliberated on principles, standards and features for an OA cartilage pathology assessment system. Using current knowledge of the pathophysiology of OA morphologic features, a proposed system was presented at OARSI 2000. Subsequently, this was widely circulated for comments amongst experts in OA pathology. An OA cartilage pathology assessment system based on six grades, which reflect depth of the lesion and four stages reflecting extent of OA over the joint surface was developed. The OARSI cartilage OA histopathology grading system appears consistent and simple to apply. Further studies are required to confirm the system's utility.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis.

            The articular surface plays an essential role in load transfer across the joint, and conditions that produce increased load transfer or altered patterns of load distribution accelerate the development of osteoarthritis (OA). Current knowledge segregates the risk factors into two fundamental mechanisms related to the adverse effects of "abnormal" loading on normal cartilage or "normal" loading on abnormal cartilage. Although chondrocytes can modulate their functional state in response to loading, their capacity to repair and modify the surrounding extracellular matrix is limited in comparison to skeletal cells in bone. This differential adaptive capacity underlies the more rapid appearance of detectable skeletal changes, especially after acute injuries that alter joint mechanics. The imbalance in the adaptation of the cartilage and bone disrupts the physiological relationship between these tissues and further contributes to OA pathology. This review focuses on the specific articular cartilage and skeletal features of OA and the putative mechanisms involved in their pathogenesis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The effect of osteoarthritis definition on prevalence and incidence estimates: a systematic review.

              To understand the differences in prevalence and incidence estimates of osteoarthritis (OA), according to case definition, in knee, hip and hand joints. A systematic review was carried out in PUBMED and SCOPUS databases comprising the date of publication period from January 1995 to February 2011. We attempted to summarise data on the incidence and prevalence of OA according to different methods of assessment: self-reported, radiographic and symptomatic OA (clinical plus radiographic). Prevalence estimates were combined through meta-analysis and between-study heterogeneity was quantified. Seventy-two papers were reviewed (nine on incidence and 63 on prevalence). Higher OA prevalences are seen when radiographic OA definition was used for all age groups. Prevalence meta-analysis showed high heterogeneity between studies even in each specific joint and using the same OA definition. Although the knee is the most studied joint, the highest OA prevalence estimates were found in hand joints. OA of the knee tends to be more prevalent in women than in men independently of the OA definition used, but no gender differences were found in hip and hand OA. Insufficient data for incidence studies didn't allow us to make any comparison according to joint site or OA definition. Radiographic case definition of OA presented the highest prevalences. Within each joint site, self-reported and symptomatic OA definitions appear to present similar estimates. The high heterogeneity found in the studies limited further conclusions. Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                +86-20-62784303 , cdz@smu.edu.cn
                +86-20-61648724 , baixc15@smu.edu.cn
                Journal
                Bone Res
                Bone Res
                Bone Research
                Nature Publishing Group UK (London )
                2095-4700
                2095-6231
                20 February 2019
                20 February 2019
                2019
                : 7
                : 5
                Affiliations
                [1 ]GRID grid.413107.0, Department of Orthopedics, Academy of Orthopedics-Guangdong Province, , The Third Affiliated Hospital of Southern Medical University, ; 510630 Guangzhou, China
                [2 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Key Laboratory of Mental Health of the Ministry of Education, Department of Cell Biology, School of Basic Medical Sciences, , Southern Medical University, ; 510515 Guangzhou, China
                [3 ]GRID grid.452734.3, Department of Orthopedic Surgery, Shantou Central Hospital, , Affiliated Shantou Hospital of Sun Yat-Sen University, ; 515041 Shantou, China
                Author information
                http://orcid.org/0000-0003-3112-9379
                Article
                41
                10.1038/s41413-018-0041-8
                6381187
                30792936
                ea198131-b182-4ea7-8e4d-b6b26665f039
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 April 2018
                : 2 November 2018
                : 14 November 2018
                Funding
                Funded by: National Natural Science Foundation of China(Grant No 81625015,81530070)and the Program for Changjiang Scholars and Innovative Research Team in University (IRT_16R37).
                Funded by: National Natural Science Foundation of China(Grant No 81601945).
                Funded by: National Natural Science Foundation of China(Grant No 81371990).
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Comments

                Comment on this article

                scite_
                0
                0
                0
                0
                Smart Citations
                0
                0
                0
                0
                Citing PublicationsSupportingMentioningContrasting
                View Citations

                See how this article has been cited at scite.ai

                scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

                Similar content458

                Cited by43

                Most referenced authors663