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Review
. 2023 Jul 7:14:1168306.
doi: 10.3389/fendo.2023.1168306. eCollection 2023.

The intricate mechanism of PLS3 in bone homeostasis and disease

Wenchao Zhong  1   2   3   4 , Janak L Pathak  4 , Yueting Liang  5   6 , Lidiia Zhytnik  1   3   7 , Gerard Pals  1   3 , Elisabeth M W Eekhoff  8   9 , Nathalie Bravenboer  2   3 , Dimitra Micha  1   3   9
Affiliations
Review

The intricate mechanism of PLS3 in bone homeostasis and disease

Wenchao Zhong et al. Front Endocrinol (Lausanne). .

Abstract

Since our discovery in 2013 that genetic defects in PLS3 lead to bone fragility, the mechanistic details of this process have remained obscure. It has been established that PLS3 variants cause syndromic and nonsyndromic osteoporosis as well as osteoarthritis. PLS3 codes for an actin-bundling protein with a broad pattern of expression. As such, it is puzzling how PLS3 specifically leads to bone-related disease presentation. Our review aims to summarize the current state of knowledge regarding the function of PLS3 in the predominant cell types in the bone tissue, the osteocytes, osteoblasts and osteoclasts. This is related to the role of PLS3 in regulating mechanotransduction, calcium regulation, vesicle trafficking, cell differentiation and mineralization as part of the complex bone pathology presented by PLS3 defects. Considering the consequences of PLS3 defects on multiple aspects of bone tissue metabolism, our review motivates the study of its mechanism in bone diseases which can potentially help in the design of suitable therapy.

Keywords: PLS3; bone cells; bone diseases; calcium regulation; mechanotransduction; osteogenesis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Structure and function of PLS3. (A) Schematic diagram of the PLS3 protein domain structure. The N-terminus of PLS3 is linked with the Ca2+-binding regulatory domain (RD), consisting of two EF-hand motifs and the calmodulin-binding motif (CBM). RD is followed by two actin-binding domains (ABD) - ABD1 and ABD2, both of which include two tandem calponin-homology (t-CH) domains, CH1, 2 and CH3,4 respectively. (B) Actin cytoskeleton remodeling by binding and bundling of PLS3. In the active state, when Ca2+ ions are absent, PLS3 binds two filamentous actin (F-actin) molecules, consisting of globular actin (G-actin) subunits. In the presence of Ca2+ ions PLS3 is inactive and the actin filament is released. (C) PLS3 and cell motility. As a component of the cytoskeleton involved in F-actin dynamics, PLS3 participates in cell migration through the extracellular matrix (ECM), focal adhesions, and actin cytoskeleton shaping near cell membranes. ABD1, 2, actin-binding domain 1, 2; CH1, 2, 3, 4, calponin-homology domain 1, 2, 3, 4; CMB, calmodulin-binding motif; ECM, extracellular matrix; EF, EF-hands domain; F-actin, filamentous actin; G-actin, globular actin; RD, regulatory domain. Figures were created with BioRender.com.
Figure 2
Figure 2
Schematic overview of the mechanosensory signaling cascade in relation to the cellular function of PLS3 in bone cells. (A) Mechanosensory function of PLS3 and calcium ion (Ca2+) oscillation in osteocytes. As a component of the mechanosensing actin cytoskeleton which is located in osteocyte dendrites, PLS3 reacts to mechanical stimuli activating a cascade of intracellular biochemical signals. Mechanical loading-induced Ca2+ oscillation triggers downstream signaling molecules of extracellular signaling pathways of bone metabolism. (B) Mechanical loading and PLS3 effects on osteoblasts and extracellular matrix mineralization. Mechanical stress in osteoblasts activates the production of signal molecules and growth factors similar to osteocytes, inducing the mineralization of the extracellular matrix. (C) TPLS3 in osteoclasts. PLS3 regulates osteoclast activity via the NFκB signaling pathway. DKK1, Dickkopf WNT Signaling Pathway Inhibitor 1; FGFs, fibroblast growth factors; FGF23 - fibroblast growth factor 23; MEPE, matrix extracellular phosphoglycoprotein; Nftac1, nuclear factor activated T cells c1; NKRF, NFκB-repressing factor; NO, nitric oxide; OPG, osteoprotegerin; PGs, prostaglandins; PLS3, t-plastin; RANK, receptor activator of nuclear factor κB; RANKL, receptor activator of nuclear factor κB ligand. Solid lines indicate pathways with solid evidence. Dashed lines indicate pathways with emerging evidence. Figures were created with BioRender.com.
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Grants and funding

The work of WZ is funded by the Guangzhou Elites Scholarship Council PhD scholarship. The work of LZ is supported by the Estonian Research Council, grant PUTJD1009.