Objectives: Chondrocyte ferroptosis contributes to osteoarthritis (OA) progression, and D‐mannose shows therapeutic value in many inflammatory conditions. Here, we investigated whether D‐mannose interferes in chondrocyte ferroptotic cell death during osteoarthritic cartilage degeneration.Materials and methods: In vivo anterior cruciate ligament transection (ACLT)‐induced OA mouse model and an in vitro study of chondrocytes in an OA microenvironment induced by interleukin‐1β (IL‐1β) exposure were employed. Combined with Epas1 gene gain‐ and loss‐of‐function, histology, immunofluorescence, quantitative RT‐PCR, Western blot, cell viability and flow cytometry experiments were performed to evaluate the chondroprotective effects of D‐mannose in OA progression and the role of hypoxia‐inducible factor 2 alpha (HIF‐2 α) in D‐mannose‐induced ferroptosis resistance of chondrocytes.Results: D‐mannose exerted a chondroprotective effect by attenuating the sensitivity of chondrocytes to ferroptosis and alleviated OA progression. HIF‐2α was identified as a central mediator in D‐mannose‐induced ferroptosis resistance of chondrocytes. Furthermore, overexpression of HIF‐2α in chondrocytes by Ad‐Epas1 intra‐articular injection abolished the chondroprotective effect of D‐mannose during OA progression and eliminated the role of D‐mannose as a ferroptosis suppressor.Conclusions: D‐mannose alleviates osteoarthritis progression by suppressing HIF‐2α‐mediated chondrocyte sensitivity to ferroptosis, indicating D‐mannose to be a potential therapeutic strategy for ferroptosis‐related diseases.

Xueman Zhou, Yingcheng Zheng, Zhenzhen Zhang, Zihan Zhang, Lina Wu, Jiaqi Liu, Wenke Yang, Jun Wang. Korean J Orthod 2022;52:150-60. https://doi.org/10.4041/kjod.2022.52.2.150

Bone stromal cells are critical for bone homeostasis and regeneration. Growing evidence suggests that non-stem bone niche cells support bone homeostasis and regeneration via paracrine mechanisms, which remain to be elucidated. Here, we show that physiologically quiescent SM22α-lineage stromal cells expand after bone injury to regulate diverse processes of intramembranous bone regeneration. The majority of SM22α-lineage cells neither act as stem cells in vivo nor show their expression patterns. Dysfunction of SM22α-lineage niche cells induced by loss of platelet-derived growth factor receptor β (PDGFRβ) impairs bone repair. We further show that PDGFRβ-triggered hydrogen sulfide (H₂S) generation in SM22α-lineage niche cells facilitates osteogenesis and angiogenesis and suppresses overactive osteoclastogenesis. Collectively, these data demonstrate that non-stem SM22α-lineage niche cells support the niche for bone regeneration with a PDGFRβ/H₂S-dependent regulatory mechanism. Our findings provide further insight into non-stem bone stromal niche cell populations and niche-regulation strategy for bone repair.