Akshay Pandey

All Publications

• Targeting an inflammation-amplifying cell population can attenuate osteoarthritis-associated pain. Arthritis research & therapy Pandey, A., Singla, M., Geller, A., Goodman, S. B., Bhutani, N. 2024; 26 (1): 53

  Abstract

  BACKGROUND: Understanding of pain in osteoarthritis, its genesis, and perception is still in its early stages. Identification of precise ligand-receptor pairs that transduce pain and the cells and tissues in which they reside will elucidate new therapeutic approaches for pain management. Our recent studies had identified an inflammation-amplifying (Inf-A) cell population that is expanded in human OA cartilage and is distinctive in the expression of both IL1R1 and TNF-R2 receptors and active Jnk signaling cascade.METHODS: In this study, we have tested the function of the cartilage-resident IL1R1+TNF-R2+ Inf-A cells in OA. We have identified that the IL1R1+TNF-R2+ Inf-A cells expand in aged mice as well as after anterior cruciate ligament tear upon tibia loading and OA initiation in mice. We targeted and modulated the Jnk signaling cascade in InfA through competitive inhibition of Jnk signaling in mice and human OA explants and tested the effects on joint structure and gait in mice.RESULTS: Modulation of Jnk signaling led to attenuation of inflammatory cytokines CCL2 and CCL7 without showing any structural improvements in the joint architecture. Interestingly, Jnk inhibition and lowered CCL2 and 7 are sufficient to significantly improve the gait parameters in treated PTOA mice demonstrating reduced OA-associated pain. Consistent with the mice data, treatment with JNK inhibitor did not improve human OA cartilage explants.CONCLUSION: These studies demonstrate that Inf-A, an articular-cartilage resident cell population, contributes to pain in OA via secretion of CCL2 and 7 and can be targeted via inhibition of Jnk signaling.

  View details for DOI 10.1186/s13075-024-03284-y

  View details for PubMedID 38368390

• Profiling joint tissues at single-cell resolution: advances and insights. Nature reviews. Rheumatology Pandey, A., Bhutani, N. 2023

  Abstract

  Advances in the profiling of human joint tissues at single-cell resolution have provided unique insights into the organization and function of these tissues in health and disease. Data generated by various single-cell technologies, including single-cell RNA sequencing and cytometry by time-of-flight, have identified the distinct subpopulations that constitute these tissues. These timely studies have provided the building blocks for the construction of single-cell atlases of joint tissues including cartilage, bone and synovium, leading to the identification of developmental trajectories, deciphering of crosstalk between cells and discovery of rare populations such as stem and progenitor cells. In addition, these studies have revealed unique pathogenetic populations that are potential therapeutic targets. The use of these approaches in synovial tissues has helped to identify how distinct cell subpopulations can orchestrate disease initiation and progression and be responsible for distinct pathological outcomes. Additionally, repair of tissues such as cartilage and meniscus remains an unmet medical need, and single-cell methodologies can be invaluable in providing a blueprint for both effective tissue-engineering strategies and therapeutic interventions for chronic joint diseases such as osteoarthritis and rheumatoid arthritis.

  View details for DOI 10.1038/s41584-023-01052-x

  View details for PubMedID 38057475

• TET1 regulates skeletal stem cell (SSC) mediated cartilage regeneration. Arthritis & rheumatology (Hoboken, N.J.) Pandey, A., Hoover, M., Singla, M., Bedi, Y., Storaci, H., Goodman, S. B., Chan, C., Bhutani, N. 2023

  Abstract

  Adult skeletal stem cells (SSC) give rise to chondrocytes, osteocytes and stromal cells as progeny have been shown to contribute to cartilage regeneration in Osteoarthritis (OA). Understanding extrinsic and intrinsic regulators of SSC fate and function can therefore identify putative candidate factors to enhance cartilage regeneration. This study explores how the DNA hydroxymethylase, TET1 regulates SSC function in OA.We investigated the differences in SSC lineage tree and differentiation potential in neonatal and adult Tet1 +/+ and Tet1-/- mice, with and without injury and upon OA induction and progression. Using RNA-seq, the transcriptomic differences between SSC and Bone, cartilage and stromal progenitor cells (BCSP) were identified in Tet1 +/+ mice and Tet1-/- mice.Loss of Tet1 skewed the SSC lineage tree by expanding the SSC pool and enhanced the chondrogenic potential of SSC and BCSP. Tet1 inhibition led to enhanced chondrogenesis in in human SSC and chondroprogenitors (CP) isolated from human cartilage. Importantly, TET1 inhibition in vivo in late stages of a mouse model of Osteoarthritis (OA) led to increased cartilage regeneration. Transcriptomic analyses of SSC and BCSP lacking Tet1 revealed pathway alterations in TGFβ signaling, melatonin degradation and cartilage development associated genes. Lastly, we report that use of hormone melatonin can dampen inflammation and improve cartilage health.While Tet1 is a broad epigenetic regulator, Melatonin can mimic the ability of TET1 inhibition to enhance the chondrogenic ability of skeletal stem cells. Melatonin administration has the potential to be an attractive stem cell based therapy for cartilage regeneration.

  View details for DOI 10.1002/art.42678

  View details for PubMedID 37610277