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Gene & Protein in Disease Comprehensive analysis of ZNF521/Zfp521

differentiation, including preosteoblasts, osteoblasts , and chondrocytes leads to decreased proliferation, accelerated
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osteocytes. The expression pattern and nuclear localization chondrocyte differentiation, and increased cell death. 19,56
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showed that Zfp521 plays a role in gene transcriptional Therefore, it can partially repair the defects of hypertrophic
regulation during osteoblast differentiation, and the loss chondrocyte differentiation, thus forming endochondral
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of Zfp521 in germ cells results in bone loss, indicating bone. PTHrP is one of the regulators of bone formation
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that Zfp521 is essential for osteoblast differentiation and in cartilage. 15,19,56 The loss of its expression or receptor
bone matrix formation. 2 (PTHR1) leads to its loss of function, inducing severe bone
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The expression of Zfp521 is suppressed by BMP2, deformity and perinatal death. Zfp521 plays an important
which can induce osteoblast differentiation and role in controlling cell differentiation 2,15,19,55 and apoptosis
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maturation. 2,15,51,55 In addition, parathyroid hormone- by mediating the effect of PTHrP on chondrocytes. As a
related protein (PTHrP)-1-34, which is conducive to cell downstream factor of PTHR1 signaling, Zfp521 is required
proliferation but antagonizes osteoblast differentiation, can for chondrocyte proliferation, differentiation, and cell
increase the expression of Zfp521 and accelerate osteoblast death. 56,57 In the absence of Zfp521, PTHrP could neither
proliferation. 15,55 Zfp521 can also interact with RUNX2 up-regulate cyclin D1 nor antagonize the expression of
to inhibit its transcriptional activity 9,24,55,56 (Figure 4). RUNX2, Ihh, and Collagen X, and Bcl2 expression is
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The specific mechanism is as follows: Zfp521 physically also decreased, while the PTHR1 signaling pathway is
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interacts with RUNX2 to antagonize RUNX2-induced stimulated. In fact, Zfp521 mediates a negative feedback
target gene activation, while RUNX2 overexpression loop that down regulates the expression of PTHR1 in pre-
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dose-dependently reverses the inhibition of Zfp521- hypertrophic chondrocytes, thereby further promoting
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induced osteoblast phenotype. 2,24,55,57,59 Therefore, Zfp521 the regulation of PTHrP on growth plate function. In
seems to inhibit the early stage of osteoblast differentiation summary, Zfp521 is a key mediator of PTHrP in regulating
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by restraining the activity of RUNX2, but it is beneficial chondrocyte differentiation (Figure 5).
to the function of osteoblasts in the later stage. 2,24,55,59 The Zfp521 also controls the transcriptional activity of
effect of high bone mass Zfp521 on mouse EBF1 may RUNX2 during chondrocyte differentiation, and its
also be involved in the regulation of Zfp521 on osteoblast inhibition of RUNX2 in chondrocytes is dependent on
differentiation and function. 2,42 HDAC4 and HDAC3, respectively. In chondrocytes,
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Zfp521 acts downstream of parathyroid hormone-related
4.3. Roles of ZNF521/Zfp521 in chondrogenic peptides, inhibiting RUNX2 and increasing growth
differentiation plate thickness. 19,47 Moreover, Zfp521 is identified as a
ZNF423, ZNF470, ZNF521, and ZNF780B may be co-inhibitor of RUNX2, 2,51,56 indicating that Zfp521 plays
involved in the physiological regulation of articular a role in blocking RUNX2 expression and activity 55-57
chondrocyte homeostasis. Zfp521 is expressed in all (Figure 5). Therefore, Zfp521 is an important regulator of
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regions of the growth plate, and the removal of Zfp521 from growth plate differentiation 19,47 and endochondral bone

Figure 4. The regulation diagram of the osteoblast maturation process. The maturation of osteoblasts is controlled by RUNX2, PTHRP-1-34, and BMP2.
BMP2 can induce the differentiation and maturation of osteoblasts while inhibiting the expression of Zfp521. Parathyroid hormone-related protein can
inhibit the differentiation and maturation of osteoblasts while promoting the transcriptional activity of Zfp521. Zfp521 can also interact with RUNX2 to
affect the RUNX2-mediated maturation process of osteoblasts.

Volume 3 Issue 3 (2024) 7 doi: 10.36922/gpd.3260