Crosstalk between YAP/TAZ and ERα in mechanical and hormonal signaling in the skeletal system

Abstract

Bone remodeling represents a dynamic equilibrium orchestrated by mechanobiological and endocrine signals, with YAP/TAZ and ERα emerging as pivotal regulators of skeletal adaptation. YAP/TAZ functions as the central mechanotransduction hub of the Hippo pathway, converting biomechanical cues, including microenvironment matrix stiffness and shear stress, into osteogenic transcriptional programs. Concurrently, ERα integrates both mechanical stimuli and estradiol (E2) signaling to coordinate osteoblast-osteoclast coupling through the transcriptional regulation of RUNX2 activity and RANKL suppression. Although increasing evidence suggests that these two systems might engage in functional crosstalk, there is still no consensus on this issue. This review synthesizes the current understanding of YAP/TAZ-ERα interactions across three dimensions: (1) mechanohormonal integration in skeletal remodeling, (2) context-dependent reciprocity in breast carcinogenesis, and (3) tissue-specific regulatory paradigms in extra-skeletal systems. Key findings reveal that YAP/TAZ and ERα exhibit both synergistic cooperation (enhanced osteogenic differentiation via promoter co-occupancy) and pathway antagonism (competitive TEAD binding), with their interaction dynamics being critically shaped by the cellular microenvironmental context. Notably, mechanical potentiation of ERα transcriptional activity requires YAP/TAZ co-activation in bone mesenchymal stem cells, whereas estrogen signaling modulates YAP mechanosensitivity through cytoskeletal remodeling. These mechanistic insights indicate that the YAP/TAZ-ERα axis is a promising therapeutic target for osteoporotic bone loss, particularly in alveolar bone preservation. By bridging endocrine and mechanobiological perspectives, this work provides a conceptual framework for developing combinatorial therapies that simultaneously address hormonal imbalance and mechanical insufficiency in skeletal pathologies.

1. Introduction

Bone remodeling represents a lifelong physiological process essential for skeletal maintenance and renewal [1,2]. This dynamic equilibrium relies on the coordinated activities of osteoblasts and osteoclasts, which are meticulously regulated by biophysical signals, biochemical signals and their interactions. Mechanical signal transduction converges on the Hippo pathway effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) molecular rheostats that translate biomechanical cues (e.g., cell density, cell area, tissue stretch, shear forces, and matrix stiffness) into transcriptional programs that govern cell behaviors, including proliferation and differentiation [3,4]. Physiological mechanical loading promotes bone anabolism through YAP/TAZ activation, whereas disuse-induced unloading precipitates rapid bone loss, underscoring their mechanosensitive regulation of skeletal integrity [5].

Among the biochemical signals, estrogen has emerged as a pivotal modulator of bone metabolism. Estrogens can be classified into a series of subtypes, of which estradiol (E2) has recently shown great potential as a major circulating estrogen in the vertebrate skeleton [6]. Research has indicated that endogenous E2 exerts dual regulatory effects through estrogen receptors (ERs), promoting osteoblastic bone formation via enhanced proliferation and survival of osteoprogenitor cells while suppressing osteoclastic bone resorption through inhibition of RANKL-mediated differentiation and induction of osteoclast apoptosis [6,7]. Notably, emerging evidence highlights the critical interplay between hormonal regulation and mechanical signaling, an indispensable determinant of skeletal adaptation to environmental biophysical stimuli [8]. The ER family, comprising the nuclear receptors ERα/ERβ and the membrane-associated G protein-coupled estrogen receptor (GPER), demonstrates functional specialization in bone homeostasis [9]. ERα has been identified as a central integrator of both hormonal and mechanical signals, orchestrating bone remodeling through multiple mechanisms: (1) modulating RUNX2 transcriptional activity to direct osteoblast differentiation; (2) suppressing mesenchymal-derived osteoclastogenic factors; and (3) enhancing osteoclast apoptosis via nongenomic pathways [10].

The emerging paradigm of YAP/TAZ-ERα crosstalk presents a compelling mechanistic link between the endocrine and biomechanical regulation of bone remodeling. Current evidence suggests that (1) both systems converge on osteoblast/osteoclast lineage commitment; (2) ERα activation modulates YAP/TAZ nuclear translocation; and (3) mechanical stimuli ...