Inflammatory macrophages interrupt osteocyte maturation and mineralization via regulating the Notch signaling pathway

Abstract

Background It is well-known that both macrophages and osteocytes are critical regulators of osteogenesis and osteoclastogenesis, yet there is limited understanding of the macrophage-osteocyte interaction, and how their crosstalk could affect bone homeostasis and mineralization. This research therefore aims to investigate the effects of macrophage polarization on osteocyte maturation and mineralization process. Methods A macrophage-derived conditioned medium based osteocyte culture was set up to investigate the impact of macrophages on osteocyte maturation and terminal mineralization. Surgically induced osteoarthritis (OA) rat model was used to further investigate the macrophage-osteocyte interaction in inflammatory bone remodeling, as well as the involvement of the Notch signaling pathway in the mineralization process. Results Our results identified that osteocytes were confined in an immature stage after the M1 macrophage stimulation, showing a more rounded morphology, higher expression of early osteocyte marker E11, and significantly lower expression of mature osteocyte marker DMP1. Immature osteocytes were also found in inflammatory bone remodeling areas, showing altered morphology and mineralized structures similar to those observed under the stimulation of M1 macrophages in vitro, suggesting that M1 macrophages negatively affect osteocyte maturation, leading to abnormal mineralization. The Notch signaling pathway was found to be down regulated in M1 macrophage-stimulated osteocytes as well as osteocytes in inflammatory bone. Overexpression of the Notch signaling pathway in osteocytes showed a significant circumvention on the negative effects from M1 macrophage. Conclusion Taken together, our findings provide valuable insights into the mechanisms involved in abnormal bone mineralization under inflammatory conditions.

Naturally derived injectable hydrogels with ROS-scavenging property to protect transplanted stem cell bioactivity for osteoarthritic cartilage repair

“…A large number of macrophages with different activation states were observed in the synovium of OA patients at different stages ( Yin J. et al, 2022 ; Jia et al, 2022 ). Among them, M1 phenotype macrophages are the main subgroups of inflammatory cytokines production, cartilage degradation, and osteophyte formation in the OA state, while M2 type macrophages have a protective effect on OA by secreting some anti-inflammatory factors ( Lv et al, 2022 ; Wang et al, 2022 ). Previous studies demonstrated that inhibiting macrophages conversion to M1 type and promoting its polarization to M2 phenotype can alleviate the synovitis and delay the progress of OA ( Zhang et al, 2018 ; Li D. et al, 2022 ; Wang and He, 2022 ).…”

Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway

“…Thus, the importance of macrophages in osteoimmunomodulation during bone regeneration cannot be overlooked [ 48 ]. CM derived from M1 macrophages could significantly inhibit osteo-/angiogenic differentiation by releasing pro-inflammatory factors [ 49 – 51 ]. In our study, we revealed that the CM collected from M1 macrophages induced by Pg.LPS indeed could inhibit osteo-/angiogenesis of PDLSCs as well as the application of quercetin reversed the above inhibitory effects, providing an optimal osteoimmunomodulatory microenvironment for PDLSCs in vitro and leading to immune-enhanced osteo-/angiogenesis.…”

Osteoimmunomodulatory Nanoparticles for Bone Regeneration

“…As mentioned, M1 macrophages dominate in the early stage of inflammation, enhancing the early commitment and recruitment of angiogenic and osteogenic precursors. In contrast, M2 macrophages function in the later stage of bone regeneration by facilitating osteocyte maturation and determining the microstructure of the newly formed bone tissue [ 140 ]. Therefore, a highly orchestrated immune response comprising sequential activation of M1 and M2 macrophages is essential for subsequent bone healing [ 141 ].…”