Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 to drive osteoarthritis

Knights, Alexander J.; Farrell, Easton C.; Ellis, Olivia M.; Lammlin, Lindsey; Junginger, Lucas; Rzeczycki, Phillip; Bergman, Rachel; Pervez, Rida; Cruz, Monique; Samani, Alexa A.; Wu, Chia‐Lung; Hankenson, Kurt D.; Maerz, Tristan

doi:10.1101/2022.05.06.489035

Cited by 4 publications

(2 citation statements)

References 69 publications

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“…In recent years, the rapid progress in single‐cell RNA sequencing, spatial transcriptomics, fate‐mapping, and multiplexed immunohistochemical technologies has revealed the unexpected diversity in macrophages. Indeed, several studies have demonstrated the synovial macrophage diversity during the pathogenesis in the OA, 224–226 and in‐depth research focusing on the distinct functions, origins, and disease kinetics of macrophage subtypes would be indispensable for targeting these versatile cells.…”

Section: Future Directionsmentioning

confidence: 99%

Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies

Yuan,

Jiang,

Yang

et al. 2024

Orthopaedic Surgery

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Osteoarthritis (OA) is the most common chronic degenerative joint disease in middle‐aged and elderly people, characterized by joint pain and dysfunction. Macrophages are key players in OA pathology, and their activation state has been studied extensively. Various studies have suggested that macrophages might respond to stimuli in their microenvironment by changing their phenotypes to pro‐inflammatory or anti‐inflammatory phenotypes, which is called macrophage polarization. Macrophages accumulate and become polarized (M1 or M2) in many tissues, such as synovium, adipose tissue, bone marrow, and bone mesenchymal tissues in joints, while resident macrophages as well as other stromal cells, including fibroblasts, chondrocytes, and osteoblasts, form the joint and function as an integrated unit. In this study, we focus exclusively on synovial macrophages, adipose tissue macrophages, and osteoclasts, to investigate their roles in the development of OA. We review recent key findings related to macrophage polarization and OA, including pathogenesis, molecular pathways, and therapeutics. We summarize several signaling pathways in macrophage reprogramming related to OA, including NF‐κB, MAPK, TGF‐β, JAK/STAT, PI3K/Akt/mTOR, and NLRP3. Of note, despite the increasing availability of treatments for osteoarthritis, like intra‐articular injections, surgery, and cellular therapy, the demand for more effective clinical therapies has remained steady. Therefore, we also describe the current prospective therapeutic methods that deem macrophage polarization to be a therapeutic target, including physical stimulus, chemical compounds, and biological molecules, to enhance cartilage repair and alleviate the progression of OA.

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Section: Future Directionsmentioning

confidence: 99%

Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies

Yuan,

Jiang,

Yang

et al. 2024

Orthopaedic Surgery

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“…Physiological data were correlated with expression data of individual genes with gene significance (GS). The visualization of the co-expression network and the recognition of the hub gene in each module were achieved through Cytosscape software v3.91 (Knights et al, 2022).…”

Section: Wgcnamentioning

confidence: 99%

Transcriptome-based analysis of key pathways relating to yield formation stage of foxtail millet under different drought stress conditions

et al. 2023

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Although foxtail millet, as small Panicoid crop, is of drought resilient, drought stress has a significant effect on panicle of foxtail millet at the yield formation stage. In this study, the changes of panicle morphology, photosynthesis, antioxidant protective enzyme system, reactive oxygen species (ROS) system, and osmotic regulatory substance and RNA-seq of functional leaves under light drought stress (LD), heavy drought stress (HD), light drought control (LDCK) and heavy drought control (HDCK) were studied to get a snap-shot of specific panicle morphological changes, physiological responses and related molecular mechanisms. The results showed that the length and weight of panicle had decreased, but with increased empty abortive rate, and then yield dropped off 14.9% and 36.9%, respectively. The photosynthesis of millet was significantly decreased, like net photosynthesis rate, stomatal conductance and transpiration rate, especially under HD treatment with reluctant recovery from rehydration. Under LD and HD treatment, the peroxidase (POD) was increased by 34% and 14% and the same as H2O2 by 34.7% and 17.2% compared with LDCK and HDCK. The ability to produce and inhibit O2- free radicals under LD treatment was higher than HD. The content of soluble sugar was higher under LD treatment but the proline was higher under HD treatment. Through RNA-seq analysis, there were 2,393 and 3,078 different genes expressed under LD and HD treatment. According to the correlation analysis between weighted gene coexpression network analysis (WGCNA) and physiological traits, the co-expression network of several modules with high correlation was constructed, and some hub genes of millet in response to drought stress were found. The expression changes relating to carbon fixation, sucrose and starch synthesis, lignin synthesis, gibberellin synthesis, and proline synthesis of millet were specifically analyzed. These findings provide a full perspective on how drought affects the yield formation of foxtail millet by constructing one work model thereby providing theoretical foundation for hub genes exploration and drought resistance breeding of foxtail millet.

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Sexual dimorphism of the synovial transcriptome underpins greater PTOA disease severity in male mice following joint injury

Bergman

Lammlin

Junginger

et al. 2022

Preprint

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Objective: To elucidate sex differences in synovitis, mechanical sensitization, structural damage, bone remodeling, and the synovial transcriptome in the anterior cruciate ligament rupture(ACLR) mouse model of post-traumatic osteoarthritis (PTOA). Methods: Male and female 12 week-old C57Bl/6 mice were randomized to noninvasive ACLR or sham (n=9/sex/group/timepoint). Knee hyperalgesia, mechanical allodynia, and intra-articular MMP activity (via intravital imaging) were measured longitudinally. Trabecular and subchondral bone remodeling and osteophyte formation were assessed by microCT. Histological scoring of PTOA and synovitis and anti-MMP13 immunostaining was performed. NaV1.8-Cre;tdTom mice were used to document localization and sprouting of nociceptors. Bulk RNAseq of synovium in sham, 7d, and 28d post-ACLR, and contralateral joints (n=6) assessed injury-induced and sex-dependent synovial gene expression. Results: Male mice exhibited worse joint damage at 7d and 28d and worse synovitis at 28d, accompanied by greater MMP activity, knee hyperalgesia, and mechanical allodynia. Females had catabolic responses in trabecular and subchondral bone after injury, whereas males exhibited greater injury-induced osteophyte formation and sclerotic remodeling of trabecular and subchondral bone. Injury-induced NaV1.8+ nociceptor sprouting in subchondral bone and medial synovium was comparable between sexes. RNAseq of synovium demonstrated that both sexes had similar injury-induced gene expression at 7d, but only female mice exhibited synovial inflammatory resolution by 28d, whereas males had persistent pro-inflammatory, pro-fibrotic, pro-neurogenic, and pro-angiogenic gene expression. Conclusion: The worse overall joint pathology and pain behavior in male mice was associated with persistent activation of synovial inflammatory, fibrotic, and neuroangiogenic processes, implicating synovitis in driving sex differences in murine PTOA.

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Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 to drive osteoarthritis

Cited by 4 publications

References 69 publications

Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies

Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies

Transcriptome-based analysis of key pathways relating to yield formation stage of foxtail millet under different drought stress conditions

Sexual dimorphism of the synovial transcriptome underpins greater PTOA disease severity in male mice following joint injury

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