Key Takeaways & Executive Findings
- •• TGF-β isoforms (β1, β2, β3) exert distinct and sometimes opposing effects on MSC osteogenic differentiation, explaining conflicting literature results. • The review systematically summarizes the molecular mechanisms of TGF-β signaling in bone metabolism, highlighting context-dependent regulation. • Discrepancies in experimental outcomes arise from differences in MSC sources, culture conditions, TGF-β concentrations, and receptor expression. • Understanding TGF-β's dual roles can guide the development of targeted therapies for bone regeneration and treatment of bone diseases.
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into cells of different lineages to form mesenchymal tissues, which are promising in regard to treatment for bone diseases. Their osteogenic differentiation is under the tight regulation of intrinsic and extrinsic factors. Transforming growth factor β (TGF-β) is an essential growth factor in bone metabolism, which regulates the differentiation of MSCs. However, published studies differ in their views on whether TGF-β signaling regulates the osteogenic differentiation of MSCs positively or negatively. The controversial results have not been summarized systematically and the related explanations are required. Therefore, we reviewed the basics of TGF-β signaling and summarized how each of three isoforms regulates osteogenic differentiation. Three isoforms of TGF-β (TGF-β1/β2/β3) play distinct roles in regulating osteogenic differentiation of MSCs. Additionally, other possible sources of conflicts are summarized here. Further understanding of TGF-β signaling regulation in MSCs may lead to new applications to promote bone regeneration and improve therapies for bone diseases.
1. Introduction
Bone tissues are essential in the human body for mechanical and metabolic functions [1]. Bone formation and resorption are dynamically balanced in a healthy skeleton, and dysregulation of the process can lead to metabolic diseases [2]. Mesenchymal stem cells (MSCs) are stem cells with the potential to differentiate into multiple forms of mesenchymal tissue, including bone tissue. MSCs have drawn much attention in regard to the treatment of bone diseases and defects, due to their pluripotency, abundant sources, and general lack of ethical problems [3, 4]. Differentiation patterns of MSCs are affected by multiple intrinsic and extrinsic factors, and the osteogenic differentiation of MSCs relates to the expression of multiple genes in a particular sequence under tight regulation [5, 6].
Transforming growth factor β (TGF-β) is a member of the TGF-β superfamily, which includes more than 30 secreted growth factors [1]. TGF-β signaling plays an essential role in many biological processes, which include development [7], immunoregulation [8], cancer progression [9], cardiovascular disease [10], bone development [11] and so on. Besides, TGF-β is also an important factor that regulates the functions of MSCs in bone metabolism [1]. Disruption of TGF-β signaling in bone metabolism underlies congenital defects, acquired diseases, and defective healing of bone tissue [12, 13]. Confusingly, the conflict viewpoints of TGF-β signaling in osteogenic differentiation of MSCs exit among some of in vitro and in vivo studies. Loss of TGF-β receptor 1 (TR1) in mice primary neonatal calvarial cells leads to inhibition of osteogenic differentiation [14]. Mesenchymal cells from mice embryo skull displayed decreased osteogenic differentiation after knockout of TGF-β receptor 2 (TR2), which is supported by down regulated expression of runt-related transcription factor 2 (Runx2), osterix (Osx), distal-less homeobox gene (Dlx5) and Msh homeobox 2.
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Erfan Wei, Menglong Hu, Likun Wu, Xingtong Pan, Qiyue Zhu, Hao Liu, Yunsong Liu (2026). TGF-β signaling regulates differentiation of MSCs in bone metabolism: disputes among viewpoints. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-024-03761-w
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Frequently Asked Questions
What is the role of TGF-β in bone metabolism?
TGF-β is a critical growth factor that regulates the differentiation of mesenchymal stem cells (MSCs) into bone-forming cells. It influences bone development, remodeling, and repair, and its dysregulation is linked to congenital defects and bone diseases.
How do TGF-β isoforms affect osteogenic differentiation?
The three isoforms (TGF-β1, β2, β3) have distinct and sometimes opposing effects on MSC osteogenic differentiation. Their specific roles depend on the cellular context, including MSC source, culture conditions, and receptor expression, which contributes to conflicting findings in the literature.
Why are there conflicting results about TGF-β and osteogenic differentiation?
Conflicting results arise from variations in experimental design, such as differences in MSC types, TGF-β concentrations, treatment duration, and the presence of other signaling molecules. Additionally, the stage of differentiation and the specific receptors activated can influence outcomes.
What are the clinical implications of this review?
Understanding the nuanced roles of TGF-β isoforms can help develop targeted strategies to enhance bone regeneration and treat bone diseases. It may also guide the optimization of MSC-based therapies by modulating TGF-β signaling appropriately.
What is the significance of TGF-β signaling in MSC-based therapies?
TGF-β signaling is a key regulator of MSC fate. By controlling its activity, researchers can potentially improve the efficiency of osteogenic differentiation for bone tissue engineering and regenerative medicine applications.
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