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P62/SQSTM1 enhances osteogenesis and attenuates inflammatory signals in bone marrow microenvironment
Dimitrios Agas1, Vladimir Gabai2, Albert A Sufianov3
1School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, (MC), Italy.
Abstract:
Bone marrow-derived mesenchymal/stromal stem cells (MSCs) became a major focus of research since the anti-inflammatory features and the osteogenic commitment of these cells can prevent the inflamm-aging and various form of osteopenia in humans and animals. We previously showed that p62/SQSTM1 plasmid can prompt release of anti-inflammatory cytokines/chemokines by MSC when injected in adult mice. Furthermore, it can enhance osteoblastogenesis at the expense of adipogenesis and ameliorate bone density and bone remodeling. On the other hand, absence of p62 partially exhausted MSC pool caused expansion of fat cells within bone marrow and pro-inflammatory mediator's accumulation. Given the critical function of p62 as molecular hub of MSC dynamics, here, using MSCs from p62 knockout adult mice, we investigated the effect of this protein on MSC survival and bone-forming molecule cascades. We found that the main osteogenic routes are impaired in absence of p62. In particular, lack of p62 can suppress Smads activation, and Osterix and CREBs expression, thus significantly modifying the schedule of MSCs differentiation. MSCs obtained from p62-/- mice have also demonstrate an amplified NFκB/ Smad1/5/8 colocalization along with NFκB activation in the nucleus, which precludes Smads binding to target promoters. Considering the "teamwork" of TGFβ, PTH and BMP2 on MSC homeostatic behavior, we consider that p62 exerts an essential role as a hub protein. Lastly, ex vivo pulsing p62-deficient MSCs, which then will be administered to a patient as a cell therapy, may be considered as a treatment for bone and bone marrow disorders.
Insights
The protein p62 is crucial for mesenchymal stem cell (MSC) function, regulating bone formation and inflammation. Its absence impairs osteogenesis and promotes inflammatory pathways, suggesting therapeutic potential for p62-manipulated MSCs in bone disorders.
Area of Science:
- Stem Cell Biology
- Bone Biology
- Molecular Medicine
Background:
- Mesenchymal stem cells (MSCs) possess anti-inflammatory and osteogenic properties beneficial for treating inflamm-aging and osteopenia.
- Previous studies demonstrated that p62/SQSTM1 plasmid enhances MSC anti-inflammatory cytokine release, promotes osteoblastogenesis, and improves bone density.
- Absence of p62 in MSCs leads to fat cell expansion and pro-inflammatory mediator accumulation in bone marrow.
Purpose of the Study:
- To investigate the role of p62 in MSC survival and bone-forming molecule cascades using MSCs from p62 knockout mice.
- To elucidate the molecular mechanisms by which p62 influences MSC differentiation and bone homeostasis.
Main Methods:
- Utilized MSCs derived from p62 knockout (p62-/-) adult mice.
- Analyzed osteogenic differentiation pathways, including Smads activation, Osterix, CREBs expression, and NFκB/Smad1/5/8 colocalization.
- Assessed the impact of p62 deficiency on key signaling pathways involved in MSC behavior.
Main Results:
- Osteogenic routes are significantly impaired in MSCs lacking p62.
- p62 deficiency suppresses Smads activation, Osterix, and CREBs expression, altering MSC differentiation timing.
- Amplified NFκB/Smad1/5/8 colocalization and nuclear NFκB activation were observed in p62-/- MSCs, inhibiting Smads binding to target promoters.
Conclusions:
- p62 acts as a critical hub protein essential for maintaining MSC homeostasis and osteogenic potential.
- The findings highlight p62's role in regulating the interplay between inflammatory and osteogenic pathways in MSCs.
- Ex vivo manipulation of p62-deficient MSCs presents a potential cell therapy strategy for bone and bone marrow disorders.
