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

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          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.

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          Most cited references47

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          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.
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            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.
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              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.
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                Author and article information

                Journal
                Bone Research
                Bone Res
                Springer Nature
                2095-6231
                December 2019
                February 20 2019
                December 2019
                : 7
                : 1
                Article
                10.1038/s41413-018-0041-8
                ea198131-b182-4ea7-8e4d-b6b26665f039
                © 2019

                http://creativecommons.org/licenses/by/4.0

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