Subchondral Bone Microarchitectural and Mineral Properties and Expression of Key Degradative Proteinases by Chondrocytes in Human Hip Osteoarthritis

Background: The purpose of this study was to investigate the relationship between the expression of key degradative enzymes by chondrocytes and the microarchitectural and mineral properties of subchondral bone across different stages of cartilage degradation in human hip osteoarthritis (OA). Methods: Osteochondral samples at different stages of cartilage degradation were collected from 16 femoral heads with OA. Osteochondral samples with normal cartilage were collected from seven femoral heads with osteoporosis. Microcomputed tomography was used for the investigation of subchondral bone microarchitecture and mineral densities. Immunohistochemistry was used to study the expression and distribution of MMP13 and ADAMTS4 in cartilage. Results: The microarchitecture and mineral properties of the subchondral plate and trabecular bone in OA varied with the severity of the degradation of the overlying cartilage. Chondrocytes expressing MMP13 and ADAMTS4 are mainly located in the upper zone(s) of cartilage regardless of the histopathological grades. The zonal expression of these enzymes in OA (i.e., the percentage of positive cells in the superficial, middle, and deep zones), rather than their overall expression (the percentage of positive cells in the full thickness of the cartilage), exhibited significant variation in relation to the severity of cartilage degradation. The associations between the subchondral bone properties and zonal and overall expression of these enzymes in the cartilage were generally weak or nonsignificant. Conclusions: Phenotypic changes in chondrocytes and remodelling of subchondral bone proceed at different rates throughout the process of cartilage degradation. Biological influences are more important for cartilage degradation at early stages, while biomechanical damage to the compromised tissue may outrun the phenotypic change of chondrocytes and is critical in the advanced stages.

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Synovium-Synovial Fluid Axis in Osteoarthritis Pathology: A Key Regulator of the Cartilage Degradation Process

Genes ◽

10.3390/genes12070989 ◽

2021 ◽

Vol 12 (7) ◽

pp. 989

Author(s):

Dhanashri Ingale ◽

Priya Kulkarni ◽

Ali Electricwala ◽

Alpana Moghe ◽

Sara Kamyab ◽

...

Keyword(s):

Synovial Fluid ◽

Early Stage ◽

Challenge Test ◽

Degradation Process ◽

Cartilage Degradation ◽

Gene Expressions ◽

Inflammatory Microenvironment ◽

Protein Levels ◽

Advanced Stages ◽

Inflammatory Milieu

Failure of conventional anti-inflammatory therapies in osteoarthritis (OA) underlines the insufficient knowledge about inflammatory mechanisms, patterns and their relationship with cartilage degradation. Considering non-linear nature of cartilage loss in OA, a better understanding of inflammatory milieu and MMP status at different stages of OA is required to design early-stage therapies or personalized disease management. For this, an investigation based on a synovium-synovial fluid (SF) axis was planned to study OA associated changes in synovium and SF along the progressive grades of OA. Gene expressions in synovial-biopsies from different grades OA patients (N = 26) revealed a peak of IL-1β, IL-15, PGE2 and NGF in early OA (Kellgren–Lawrence (KL) grade-I and II); the highest MMP levels were found in advanced stages (KL grade-III and IV). MMPs (MMP-1, 13, 2 and 9) abundance and FALGPA activity estimated in forty SFs of progressive grades showed the maximum protein levels and activity in KL grade-II and III. In an SF challenge test, SW982 and THP1 cells were treated with progressive grade SFs to study the dynamics of MMPs modulation in inflammatory microenvironment; the test yielded a result pattern, which matched with FALGPA and the protein-levels estimation. Inflammatory mediators in SFs served as steering factor for MMP up-regulation. A correlation-matrix of IL-1β and MMPs revealed expressional negative correlation.

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SOST Deficiency Aggravates Osteoarthritis in Mice by Promoting Sclerosis of Subchondral Bone

BioMed Research International ◽

10.1155/2019/7623562 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8

Author(s):

Jingyu Li ◽

Junjie Xue ◽

Yan Jing ◽

Manyi Wang ◽

Rui Shu ◽

...

Keyword(s):

Subchondral Bone ◽

Cruciate Ligament ◽

Cartilage Degradation ◽

Cell Number ◽

Blue Staining ◽

Sham Operation ◽

Knee Oa ◽

Sost Gene ◽

Bone Sclerosis ◽

The Difference

As the initial part in the development of osteoarthritis (OA), subchondral bone sclerosis has been considered to be initiated by excess mechanical loading and proven to be correlated to other pathological changes. Sclerostin, which is an essential mechanical stress response protein, is encoded by the SOST gene. It is expressed in osteocytes and mature chondrocytes and has been proven to be closely correlated to OA. However, the relationship and mechanism between the SOST gene and the development of OA remain unclear. The aim of the present study was to investigate the role of the SOST gene in OA pathogenesis in the subchondral bone. A knee anterior cruciate ligament transection (ACLT) mouse osteoarthritis (OA) model on SOST-knockout (SOST KO) and wild-type (WT) mice was established. The pathogenic and phenotypic changes in the subchondral bone were investigated by histology, micro-CT, immunohistochemistry, TRAP staining, Masson staining, and Toluidine blue staining. It was found that sclerostin expression decreased in both the calcified cartilage and mineralized subchondral structures during the development of OA. Joint instability induced a severe cartilage degradation phenotype, with higher OARSI scores in SOST KO mice, when compared to WT mice. SOST KO mice with OA exhibited a higher BMD and BV/TV ratio, as well as a higher rate of bone remodeling and TRAP-positive cell number, when compared to the WT counterparts, but the difference was not significant between the sham-operation groups. It was concluded that loss of sclerostin aggravates knee OA in mice by promoting subchondral bone sclerosis and increasing catabolic activity of cartilage.

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Difference in subchondral cancellous bone between postmenopausal women with hip osteoarthritis and osteoporotic fracture: Implication for fatigue microdamage, bone microarchitecture, and biomechanical properties

Arthritis & Rheumatism ◽

10.1002/art.34670 ◽

2012 ◽

Vol 64 (12) ◽

pp. 3955-3962 ◽

Cited By ~ 29

Author(s):

Zhan-Chun Li ◽

Li-Yang Dai ◽

Lei-Sheng Jiang ◽

Shijing Qiu

Keyword(s):

Postmenopausal Women ◽

Cancellous Bone ◽

Osteoporotic Fracture ◽

Bone Microarchitecture ◽

Hip Osteoarthritis ◽

Biomechanical Properties ◽

Fatigue Microdamage

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Relationship between articular cartilage damage and subchondral bone properties and meniscal ossification in the Dunkin Hartley guinea pig model of osteoarthritis

Scandinavian Journal of Rheumatology ◽

10.3109/03009742.2011.571218 ◽

2011 ◽

Vol 40 (5) ◽

pp. 391-399 ◽

Cited By ~ 19

Author(s):

JS Thomsen ◽

TS Straarup ◽

CC Danielsen ◽

H Oxlund ◽

A Brüel

Keyword(s):

Articular Cartilage ◽

Guinea Pig ◽

Subchondral Bone ◽

Cartilage Damage ◽

Pig Model ◽

Articular Cartilage Damage ◽

Bone Properties ◽

Guinea Pig Model

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Systematic Analysis of Transcriptomic Profile of Chondrocytes in Osteoarthritic Knee Using Next-Generation Sequencing and Bioinformatics

Journal of Clinical Medicine ◽

10.3390/jcm7120535 ◽

2018 ◽

Vol 7 (12) ◽

pp. 535 ◽

Cited By ~ 5

Author(s):

Yi-Jen Chen ◽

Wei-An Chang ◽

Ling-Yu Wu ◽

Ya-Ling Hsu ◽

Chia-Hsin Chen ◽

...

Keyword(s):

Next Generation Sequencing ◽

Family Member ◽

Subchondral Bone ◽

Joint Pain ◽

Expression Patterns ◽

Cartilage Damage ◽

Phenotypic Change ◽

Next Generation ◽

Arthritic Joint ◽

Generation Sequencing

The phenotypic change of chondrocytes and the interplay between cartilage and subchondral bone in osteoarthritis (OA) has received much attention. Structural changes with nerve ingrowth and vascular penetration within OA cartilage may contribute to arthritic joint pain. The aim of this study was to identify differentially expressed genes and potential miRNA regulations in OA knee chondrocytes through next-generation sequencing and bioinformatics analysis. Results suggested the involvement of SMAD family member 3 (SMAD3) and Wnt family member 5A (WNT5A) in the growth of blood vessels and cell aggregation, representing features of cartilage damage in OA. Additionally, 26 dysregulated genes with potential miRNA–mRNA interactions were identified in OA knee chondrocytes. Myristoylated alanine rich protein kinase C substrate (MARCKS), epiregulin (EREG), leucine rich repeat containing 15 (LRRC15), and phosphodiesterase 3A (PDE3A) expression patterns were similar among related OA cartilage, subchondral bone and synovial tissue arrays in Gene Expression Omnibus database. The Ingenuity Pathway Analysis identified MARCKS to be associated with the outgrowth of neurite, and novel miRNA regulations were proposed to play critical roles in the pathogenesis of the altered OA knee joint microenvironment. The current findings suggest new perspectives in studying novel genes potentially contributing to arthritic joint pain in knee OA, which may assist in finding new targets for OA treatment.

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Attenuation of Trauma-induced Osteoarthritis by Repetitive Intra-articular Administration of Peripheral Blood Derived Mesenchymal Stem Cells

10.21203/rs.3.rs-910616/v1 ◽

2021 ◽

Author(s):

Weiping Lin ◽

Zhengmeng Yang ◽

Liu Shi ◽

Haixing Wang ◽

Qi Pan ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Articular Cartilage ◽

Subchondral Bone ◽

Peripheral Blood ◽

Cartilage Degradation ◽

Cartilage Tissue ◽

Synovial Joint ◽

Post Surgery ◽

Sham Surgery

Abstract Background: Osteoarthritis (OA) is a chronic joint disease, characterized by articular cartilage degradation, subchondral bone hardening, and inflammation of the whole synovial joint. There is no pharmacological treatment in slowing down OA progression, leading to costly surgical interventions eventually. Cell therapy using chondrocytes or progenitor cells from different sources has been reported in clinical trials for OA management with some success, but outcomes are varied. Peripheral blood derived mesenchymal stem cells (PB-MSCs) are promising cells owing to their easy collection, superior migration, and differentiation potentials. In the current study, we evaluated the effect of intra-articular administration of PB-MSCs on the progression of OA in mice.Methods: C57BL/6J mice (8-10 weeks old male) were subjected to destabilization of the medial meniscus surgeries (DMM) on their right joints following protocols as previously reported. The mice after DMM were randomly treated with saline (vehicle control), PB-MSCs, or adipose tissue derived MSCs (AD-MSCs) (n = 7 per group). The mice treated with sham surgery were regarded as sham controls (n = 7). PB-MSCs and AD-MSCs were harvested and cultured according to previous published protocols, and pre-labeled with BrdU for 48 h before use. PB-MSCs or AD-MSCs (5 × 105 cells/mouse; passage 3~5) were injected into the right knee joints thrice post-surgery (except sham surgery group). The mice were euthanized at 8 weeks post-surgery and knee joint samples were collected for micro-CT and histological examinations.Results: PB-MSCs administration significantly reduced hardening of subchondral bone comparing to vehicle controls. Safranin O staining showed that PB-MSCs treatment ameliorated degeneration of articular cartilage, which is comparable to AD-MSCs treatment. The expression of catabolic marker MMP13 was significantly reduced in articular cartilage of PB-MSCs-treated groups comparing to vehicle controls. Co-expression of BrdU and Sox9 were detected, indicating injected PB-MSCs differentiated towards chondrocytes in situ. Reduced level of IL-6 in the peripheral sera of PB-MSCs- and AD-MSCs-treated mice was also determined. Conclusions: Repetitive administration of PB-MSCs or AD-MSCs halted OA progression through inhibiting cartilage degradation and inflammation. PB-MSCs may become a promising cell source for cartilage tissue repair and alleviation of OA progression.

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Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis

Cells ◽

10.3390/cells9040927 ◽

2020 ◽

Vol 9 (4) ◽

pp. 927 ◽

Cited By ~ 5

Author(s):

Szu-Yu Chien ◽

Chun-Hao Tsai ◽

Shan-Chi Liu ◽

Chien-Chung Huang ◽

Tzu-Hung Lin ◽

...

Keyword(s):

Articular Cartilage ◽

Signaling Pathways ◽

Bone Remodeling ◽

Subchondral Bone ◽

Bone Destruction ◽

Cartilage Degeneration ◽

Cartilage Degradation ◽

Mitogen Activated Protein Kinase ◽

Bone Morphogenetic Protein 2 ◽

Joint Disease

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.

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Interspecies comparison of subchondral bone properties important for cartilage repair

Journal of Orthopaedic Research® ◽

10.1002/jor.22740 ◽

2014 ◽

Vol 33 (1) ◽

pp. 63-70 ◽

Cited By ~ 26

Author(s):

Anik Chevrier ◽

Ahou S. M. Kouao ◽

Genevieve Picard ◽

Mark B. Hurtig ◽

Michael D. Buschmann

Keyword(s):

Cartilage Repair ◽

Subchondral Bone ◽

Interspecies Comparison ◽

Bone Properties

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Noncoding RNAs in subchondral bone osteoclast function and their therapeutic potential for osteoarthritis

Arthritis Research & Therapy ◽

10.1186/s13075-020-02374-x ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Li Duan ◽

Yujie Liang ◽

Xiao Xu ◽

Jifeng Wang ◽

Xingfu Li ◽

...

Keyword(s):

Bone Resorption ◽

Bone Remodeling ◽

Subchondral Bone ◽

Therapeutic Potential ◽

Osteoclast Differentiation ◽

Noncoding Rnas ◽

Cartilage Degradation ◽

Joint Disease ◽

Molecular Signaling ◽

Osteoclast Function

AbstractOsteoclasts are the only cells that perform bone resorption. Noncoding RNAs (ncRNAs) are crucial epigenetic regulators of osteoclast biological behaviors ranging from osteoclast differentiation to bone resorption. The main ncRNAs, including miRNAs, circRNAs, and lncRNAs, compose an intricate network that influences gene transcription processes related to osteoclast biological activity. Accumulating evidence suggests that abnormal osteoclast activity leads to the disturbance of subchondral bone remodeling, thus initiating osteoarthritis (OA), a prevalent joint disease characterized mainly by cartilage degradation and subchondral bone remodeling imbalance. In this review, we delineate three types of ncRNAs and discuss their related complex molecular signaling pathways associated with osteoclast function during bone resorption. We specifically focused on the involvement of noncoding RNAs in subchondral bone remodeling, which participate in the degradation of the osteochondral unit during OA progression. We also discussed exosomes as ncRNA carriers during the bone remodeling process. A better understanding of the roles of ncRNAs in osteoclast biological behaviors will contribute to the treatment of bone resorption-related skeletal diseases such as OA.

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