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Nox4 expression in osteo-progenitors controls bone development in mice during early life

ABSTRACT: Tightly regulated and cell-specific NADPH-oxidases (Nox) represent one of the major sources of reactive oxygen species (ROS) signaling molecules that are involved in tissue development and stem cell self-renewal. We have characterized the role of Nox4 in osteo-progenitors during postnatal bone development. Nox4 expression in bone and ROS generation were increased during early osteoblast differentiation and bone development. Stromal osteoblastic cell self-renewal, proliferation and ROS production were significantly lower in samples from whole body Nox4 knockout mice (Nox4-/-) and conditional knockout (CKO) mice with depletion of Nox4 in the limb bud mesenchyme compared with those from control mice (Nox4fl/fl), but they were reversed after 9 passages. In both sexes, bone volume, trabecular number and bone mineral density were significantly lower in 3-week old CKO and Nox4-/- mice compared with Nox4fl/fl controls. This was reflected in serum levels of bone formation markers alkaline phosphatase (ALP) and procollagen 1 intact N-terminal propeptide (P1NP). However, under-developed bone formation in 3-week old CKO and Nox4-/- mice quickly caught up to levels of control mice by 6-week of age, remained no different at 13-week of age, and was reversed in 32-week old male mice. Osteoclastogenesis showed no differences among groups, however, CTX1 reflecting osteoclast activity was significantly higher in 3-week old male CKO and Nox4-/- mice compared with control mice, and significantly lower in 32-week old Nox4-/- mice compared with control mice. These data suggest that Nox4 expression and ROS signaling in bone and osteoblastic cells coordinately play a role on osteoblast differentiation, proliferation and maturation.

ORGANISM(S): Mus musculus

PROVIDER: GSE195454 | GEO | 2022/06/22

REPOSITORIES: GEO

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Project description:The trimeric thrombospondin homologs, TSP1 and TSP2, are both components of bone tissue and contribute in redundant and distinct ways to skeletal physiology. The functional effects of combined TSP1 and TSP2 deficiency remain to be elucidated. Here, we examined the spectrum of detergent soluble proteins in diaphyseal cortical bone of growing (6-week old) male and female mice deficient in both thrombospondins (double knockout (DKO)). Equal amounts of detergent soluble cortical bone protein were subject to Tandem Mass Tags (TMT) quantitative proteomics. 3,429 proteins met the selection criteria (FDR≤ 1% and 2 peptide spectral matches). 181 proteins were differentially abundant in both male and female DKO bones (≥1.95 fold or ≤0.55 fold compared to wild-type). Physiologically relevant annotation terms identified by Ingenuity Pathway Analysis included “ECM degradation” and “Quantity of Monocytes.” Manual inspection revealed that a number of proteins with shared expression among osteoclasts and osteocytes were reduced in DKO bones. To associate changes in protein content with phenotype, we examined 12-week old male DKO and WT mice. DKO mice were smaller than WT. DKO femora had reduced cross-sectional area with a flattened, less circular cross-section. DKO bones were less stiff in bending, but this reduction was disproportionate to the decreases in bending moment of inertia on nanoCT leading to a modest increase in predicted modulus (stiffness/bending moment). DKO displayed a lower ultimate load along with increases in both ultimate displacement and yield displacement. The ratio of ultimate displacement to yield displacement was actually higher in DKO, suggesting that decreased yield displacement does not account entirely for the reduction in ultimate displacement. Together, these mechanical attributes suggest compensation for small bone size through mechanisms that are not explained by nanoCT structural analysis. DKO mice also exhibited reductions in trabecular bone mass, which were surprisingly associated with increased osteoblast numbers and osteoid surface. Marrow-derived colony forming unit-fibroblastic was reduced in DKO mice. Together our data suggest that when both TSP1 and TSP2 are absent, a unique bone phenotype not predicted by the single knockouts, is manifested

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Nox4 expression in osteo-progenitors controls bone development in mice during early life

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