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Age‐induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases the risk for bone fractures. Despite epidemiology studies reporting concurrent development of vascular and bone diseases in the elderly, the underlying mechanisms for the vascular‐bone cross‐talk in aging are largely unknown. In this study, we show that accelerated endothelial aging deteriorates bone tissue through paracrine repression of Wnt‐driven‐axis in BMSCs. Here, we utilize physiologically aged mice in conjunction with our transgenic endothelial progeria mouse model (Hutchinson‐Gilford progeria syndrome; HGPS) that displays hallmarks of an aged bone marrow vascular niche. We find bone defects associated with diminished BMSC osteogenic differentiation that implicate the existence of angiocrine factors with long‐term inhibitory effects. microRNA‐transcriptomics of HGPS patient plasma combined with aged‐vascular niche analyses in progeria mice reveal abundant secretion of Wnt‐repressive microRNA‐31‐5p. Moreover, we show that inhibition of microRNA‐31‐5p as well as selective Wnt‐activator CHIR99021 boosts the osteogenic potential of BMSCs through de‐repression and activation of the Wnt‐signaling, respectively. Our results demonstrate that the vascular niche significantly contributes to osteogenesis defects in aging and pave the ground for microRNA‐based therapies of bone loss in elderly. [ABSTRACT FROM AUTHOR]

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F- actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients., Introduction Hutchinson-Gilford progeria syndrome (HGPS) is a rare, progressive, premature aging disease characterized by growth retardation, alopecia, loss of subcutaneous fat, aged-looking skin, bone abnormalities, and osteoporosis (1-3). A hallmark [...]

Lamina-associated polypeptide (LAP) 2[alpha] is a non-membrane-bound LAP2 isoform that forms complexes with nucleoplasmic A-type lamins. In this study, we show that the overexpression of LAP20[alpha] in fibroblasts reduced proliferation and delayed entry into the cell cycle from a GO arrest. In contrast, stable down-regulation of LAP20[alpha] by RNA interference accelerated proliferation and interfered with cell cycle exit upon serum starvation. The LAP2[alpha]-linked cell cycle phenotype is mediated by the retinoblastoma (Rb) protein because the LAP2[alpha] COOH terminus directly bound Rb, and overexpressed LAP2e[alpha] inhibited E2F/Rb-dependent reporter gene activity in G1 phase in an Rb-dependent manner. Furthermore, LAP2e[alpha] associated with promoter sequences in endogenous E2F/Rb-dependent target genes in vivo and negatively affected their expression. In addition, the expression of LAP2[alpha] in proliferating preadipocytes caused the accumulation of hypophosphorylated Rb, which is reminiscent of noncycling cells, and initiated partial differentiation into adipocytes. The effects of LAP20[alpha] on cell cycle progression and differentiation may be highly relevant for the cell-and tissue-specific phenotypes observed in laminopathic diseases.

In vitro assays demonstrate that lamino-associated polypeptides (LAPs), 1A and 1B in particular, bind to lamins A and C and B, but LAP 2 relates with lamin B and binds to mitotic chromosomes. LAP 2 may be crucial to the early processes in nuclear envelope reorganization, and LAP 2 and LAP 1 may be concerned with linking lamino to the nuclear envelope. Before the organization of a majority of lamins, during late anaphase, LAP 2 relates with chromosomes. LAPs 1A, 1B, 1C and 2 are integral membrane proteins of the nuclear envelope related to the nuclear lamina.