Cellular TEAD1 activity as predictor for osteoblast lineage speciation and metabolic bone disease

Atenisa Caci*

*Corresponding author for this work

Research output: ThesisPh.D. thesis

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Abstract

Osteoporosis is a disorder in which bone mass and quality decrease, increasing the chance of fracture, which has a significant impact on life quality. Bone, being a dynamic tissue undergoes continuous remodeling through the combined action of bone-forming osteoblasts and bone-resorbing osteoclasts, with a defect in the first having been shown to be crucial for age-related bone loss. Clinically, bone loss is strongly associated with increased marrow fat content, not only in subjects with osteoporosis but also in conditions such as type I diabetes, anorexia nervosa, and unloading. Osteoblasts, as well as adipocytes, derive from multipotent stromal cells implying that changes in the rate of stromal progenitors undergoing osteoblast or adipocyte differentiation might be causative for bone loss. Consequently, molecular factors that control the lineage commitment of stromal cells present an appealing target for clinical therapies focused on bone regeneration and fighting bone metabolic diseases. The differentiation of stromal cells into specific cell lineages is regulated by lineage-selective transcription factor networks that activate cell-type specific gene programs while repressing genes important for stem cell state. In a recent study, TEAD transcription factors have been suggested to be part of a huge transcriptional network in stromal cells that is crucial for osteoblast differentiation while inhibiting the differentiation of fat cells. TEADs transcription factors recruit YAP1 and TAZ, transcriptional coactivators under the control of the Hippo signaling pathway, known for its  ability to promote osteogenic differentiation and inhibit adipogenic differentiation. We, therefore, propose TEAD transcription factors to be molecular rheostats of lineage commitment in stromal cells. The chromatin binding dynamics of YAP and TEAD1 imply a robust link of the Hippo signaling pathway with the stem cell gene program and the activation of osteoblast-selective genes. Both the binding of YAP1 and TEAD1 to chromatin is highly dependent on the nuclear abundance of YAP, indicating a cofactor-dependent dissociation of TEAD1. Cells treated with compounds that disrupt protein interactions of YAP1 or TEADs showed a diminished osteogenic capacity, suggesting TEADs as mediators of YAP1 action during osteoblast differentiation. Testing whether loss of TEAD1 could mimic the effect of YAP1 deficiency in human cells, we could show that knockout but not siRNA-mediated silencing abolished osteogenic differentiation. Interestingly, primary cells from mice derived from bone and marrow compartments showed strong differences in TEAD1 dependency of osteogenic differentiation, with bone-derived cells requiring TEAD1 while marrow-derived cells showed elevated osteogenic commitment upon TEAD1 ablation. Using, osteoblast-specific Tead1 knockout mice, we could not confirm the role of TEAD1 in the acquisition of bone mass and structure as well as in bone regeneration upon mono cortical defect. Taken together, chromatin binding dynamics and pharmacological inhibition of YAP1-TEAD interactions indicate a putative role of TEAD1 transcription factor in the osteogenic commitment of stromal cells. However, the impact of genetic ablation of TEAD1 on osteoblast differentiation is highly context-specific in vitro and not conclusive in vivo. We propose that TEAD transcription factors, most likely in a highly redundant manner, mediate the effects of the Hippo signaling pathway on lineage commitment of stromal cells.
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Rauch, Alexander, Supervisor
Date of defence18. Jun 2024
Publisher
DOIs
Publication statusPublished - 1. May 2024

Keywords

  • Osteoblast
  • Adipocyte
  • MSCs
  • TEAD1
  • YAP1
  • Hippo signaling

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