P62 deficiency shifts mesenchymal/stromal stem cell commitment toward adipogenesis and disrupts bone marrow homeostasis in aged mice

Abstract

With advancing age have been observed bone and bone marrow phenotypic alterations due to the impaired bone tissue homeostatic features, involving bone remodeling, and bone marrow niche ontogeny. The complex “inflamm‐aging” pathological scenario that culminates with osteopenia and mesenchymal/stromal and hematopoietic stem cell commitment breakdown, is controlled by cellular and molecular intramural components comprising adapter proteins such as the sequestosome 1 (p62/SQSTM1). p62, a “multiway function” protein, has been reported as an effective anti‐inflammatory, bone‐building factor. In this view, we considered for the first time the involvement of p62 in aging bone and bone marrow of 1 year and 2 years p62−/− mice. Interestingly, p62 deficiency provoked accelerated osteopenia and impaired niche operational activities within the bone marrow. The above findings unearthed the importance of p62 in mesenchymal stem cell maintenance/differentiation schedule in old animals and provide, at least in part, a mechanistic scenario of p62 action.

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

“…In particular, adipo-osteogenic balance is reciprocally maintained. 5,6 Recently, the regulation of differentiation by several lipid species has been suggested as an important differentiation control mechanism. 2 Dysregulation of this balance is linked to pathophysiologic states.…”

“…Although each lineage‐specific factor is needed for fate determination, the exact governing mechanism is not clearly defined. Several stem cell fate‐determining factors have been newly discovered, and this information provides new insight into the differentiation and treatment of metabolic bone diseases …”

“…Several stem cell fate-determining factors have been newly discovered, and this information provides new insight into the differentiation and treatment of metabolic bone diseases. 5,6 Recently, the regulation of differentiation by several lipid species has been suggested as an important differentiation control mechanism. Mammalian cells produce a large number of lipid species that actively turn over and are involved in essential cellular processes by moving between cellular compartments.…”

The Hematopoietic Bone Marrow Niche Ecosystem

“…Recent studies have further shown that aging is also associated with chronic remodeling of the niche, which involves an increase in adipogenic cells (Sanchez-Aguilera et al, 2014). This fatty degeneration has been attributed to a decline in osteogenic cell fate determination (Nishikawa et al, 2010;Yu et al, 2018;Kato et al, 2019;Lacava et al, 2019) which switches mesenchymal precursors to an adipogenic state, further associated with an increase in stromal senescence (Gnani et al, 2019), loss of niche-forming endomucin-positive (EMCN + ) CD31 hi "Type H" vessels (Kusumbe et al, 2014), and b3adrenergic innervation (Maryanovich et al, 2018;Ho et al, 2019). Added complexity of this system is that niche remodeling is associated with an altered lineage output, including increased myelopoiesis, thrombopoiesis, and clonal hematopoiesis.…”

Loss of p62 impairs bone turnover and inhibits PTH‐induced osteogenesis

“…In accordance with this hypothesis, Valencia et al (2014) showed that p62 plays an anticancer activity by inhibiting the inflammation in the tumor microenvironment. Furthermore, we recently demonstrated a significant adipocyte infiltration associated with an increase of pro-inflammatory cytokines in the bone marrow of p62 −/− aged mice (Lacava et al, 2019). Thus, although the recent research appear to converge in considering that p62, at least in part, contrasts inflammation, the functions of this protein on bone metabolism, remain at the moment, incompletely elucidated.…”