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 language | English |
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Date of defence | 18. Jun 2024 |
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DOIs | |
Publication status | Published - 1. May 2024 |
Keywords
- Osteoblast
- Adipocyte
- MSCs
- TEAD1
- YAP1
- Hippo signaling