Subchondral bone microenvironment in osteoarthritis and pain

Yan, Hu; Chen, Xiao; Sicheng, Wang; Jing, Yingying; Su, Jiacan

doi:10.1038/s41413-021-00147-z

Cited by 224 publications

(233 citation statements)

References 218 publications

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“…Since OA is a disease of the whole joint and OA progression and pain has been associated with aberrant subchondral bone remodeling and innervation 39, 40 , we utilized uCT to evaluate the subchondral bone in WT and Il6 −/− knees following DMM/sham surgeries. At 8-weeks post-DMM injury, we observed subchondral bone sclerosis in both WT and Il6 −/− mice (Figure 3), suggesting that removal of Il6 does not attenuate subchondral sclerosis, and that the reduced PTOA-associated pain and cartilage degradation in Il6 −/− mice does not occur due to corrections in subchondral bone remodeling.…”

Section: Resultsmentioning

confidence: 99%

Interleukin-6 Signaling Mediates Cartilage Degradation and Pain in Post-Traumatic Osteoarthritis

Liao

Ren

Luo

et al. 2021

Preprint

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Osteoarthritis (OA) and post-traumatic OA (PTOA) are prevalent joint disorders and leading causes of chronic pain. The disease pathology of OA/PTOA is caused by imbalanced catabolic and anabolic responses and pro-inflammatory changes; however, their connection to pain is not well studied. Since IL-6 is involved in cartilage degradation and conditions of inflammatory pain, we set out to identify whether IL-6 and IL-6 signaling mechanisms contribute to both PTOA-associated cartilage degradation and pain. We performed a modified destabilization of the medial meniscus (DMM) surgery, a model of PTOA, on conventional IL-6 KO and control mice and assessed both cartilage degradation and pain-associated phenotypes. Genetic removal of Il6 in males attenuates PTOA-associated cartilage catabolism, decreases innervation of soft tissues associated with the knee joint, and reduces nociceptive pain signaling, without improving subchondral bone sclerosis or chondrocyte apoptosis. We further demonstrate that specific downstream mediators of IL-6 signaling, the Janus kinases (JAKs), are critical in regulating both cartilage catabolism and pain signaling. We identified STAT3 as a key regulator of cartilage catabolism downstream of JAK; however, inhibition of STAT3 decreases cartilage anabolism while enhancing pain signals. ERK was found to be important for neurite outgrowth and pain signaling; however, inhibition of ERK was less effective in reducing cartilage catabolism. Therefore, our data demonstrate that IL-6 mediates both PTOA-associated cartilage degradation and pain, and provides critical details regarding the downstream mediators of IL-6 signaling as therapeutic targets for disease-modifying osteoarthritis drugs.

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Section: Resultsmentioning

confidence: 99%

Interleukin-6 Signaling Mediates Cartilage Degradation and Pain in Post-Traumatic Osteoarthritis

Liao

Ren

Luo

et al. 2021

Preprint

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“… 87 Activation of osteoclasts can result in pain genesis through developing acidic conditions at the osteochondral junction, thereby activating acid-sensing receptors of sensory neurons. 88 , 89 Subchondral bone also undergoes remarkable alterations in both composition and structural organization, leading to adverse effects on the overlying articular cartilage. 90 Therefore, targeting the pathways that modify subchondral bone turnover is an attractive option for DMOAD research.…”

Section: Bone-driven Endotypementioning

confidence: 99%

“… 90 Therefore, targeting the pathways that modify subchondral bone turnover is an attractive option for DMOAD research. 89 The pharmaceutical drugs in phase 2 and 3 stages of development for bone-driven endotype are summarized in Table 2 .…”

Section: Bone-driven Endotypementioning

confidence: 99%

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

Oo¹,

Little²,

Duong³

et al. 2021

DDDT

163

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Osteoarthritis (OA) is a complex heterogeneous articular disease with multiple joint tissue involvement of varying severity and no regulatory-agency-approved diseasemodifying drugs (DMOADs). In this review, we discuss the reasons necessitating the development of DMOADs for OA management, the classifications of clinical phenotypes or molecular/mechanistic endotypes from the viewpoint of targeted drug discovery, and then summarize the efficacy and safety profile of a range of targeted drugs in Phase 2 and 3 clinical trials directed to cartilage-driven, bone-driven, and inflammation-driven endotypes. Finally, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers.

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“…OA severely affects patients' quality of life and cause a huge socioeconomic burden. 1,2 Chondrocytes are the only cell type in articular cartilage. Chondrocytes secrete a series of cytokines to regulate the growth, distribution and reconstruction of cartilage matrix.…”

Section: Introductionmentioning

confidence: 99%

Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo

Pang¹,

Jiang²,

Zhu³

et al. 2021

DDDT

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Oxidative stress-induced chondrocyte apoptosis and extracellular matrix (ECM) degradation plays an important role in the progression of osteoarthritis (OA). Bardoxolone methyl (BM), a semisynthetic triterpenoid, exerts strong effect against oxidative stress. The purpose of the present study was to determine the effectiveness of bardoxolone-methyl (BM) in preventing oxidative stress-induced chondrocyte apoptosis and extracellular ECM degradation in vitro and the role of alleviating OA progression in vivo. Methods: Oxidative damage was induced by 25 mM tert-butyl hydroperoxide (TBHP) for 24 h in rat chondrocytes. 0.025 and 0.05 µM bardoxolone-methyl (BM) were used in vitro treatment. Ex-vivo cartilage explant model was established to evaluate the effect of BM on oxidative stress-induced ECM degradation. The mouse OA model was induced by surgical destabilization of the medial meniscus. Results: In vitro, 0.025 and 0.05 µM BM reduced TBHP-induced excessive ROS generation, improved cell viability, increased malondialdehyde level and decreased superoxide dismutase level. 0.025 and 0.05 µM BM prevented TBHP-induced mitochondrial damage and apoptosis in chondrocytes BM activated heme oxygenase-1 (HO-1)/NADPH quinone oxidoreductase 1 (NOQ1) signaling pathway through targeting nuclear factor erythroid derived-2-related factor 2 (Nrf2). Additionally, BM treatment enhanced the expression levels of aggrecan and collagen II and inhibited the expression levels of matrix metalloproteinase 9 (MMP 9), MMP 13, Bax and cleaved-caspase-3. BM increased proteoglycan staining area and IOD value in ex vivo cultured experiment cartilage explants and improved the OARSI score, stands, max contact mean intensity, print area and duty cycle in mouse OA model. Conclusion: BM prevented oxidative stress-induced chondrocyte apoptosis and ECM degradation in vitro and alleviated OA in vivo, suggesting that BM serves as an effective drug for treatment with OA.

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Subchondral bone microenvironment in osteoarthritis and pain

Cited by 224 publications

References 218 publications

Interleukin-6 Signaling Mediates Cartilage Degradation and Pain in Post-Traumatic Osteoarthritis

Interleukin-6 Signaling Mediates Cartilage Degradation and Pain in Post-Traumatic Osteoarthritis

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo

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