MEPE

Official Full Name

matrix extracellular phosphoglycoprotein

Organism

Homo sapiens

GeneID

56955

Background

This gene encodes a secreted calcium-binding phosphoprotein that belongs to the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family of proteins. Members of this family are components of the extracellular matrix of bone and dentin and regulate bone mineralization. Deficiency of a similar protein in mouse results in increased bone mass. Mice lacking this gene are resistant to aging-related trabecular bone loss. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

Synonyms

OF45;

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Detailed Information

The matrix extracellular phosphor glycoprotein (MEPE) is a highly expressed protein found in tumor-induced osteomalacia (TIO). It plays an important role in matrix calcification, regulation of osteoblasts and osteoclast function. As a member of the SIBLING protein family, MEPE protein plays an irreplaceable role in the formation and development of bones and teeth, and is also an important biomolecule regulating the phosphate balance in the body.

It was initially discovered that MEPE is highly expressed in tumor tissues of patients with TIO, and that patients with hypophosphatemia are relieved after tumor resection, so it is considered that MEPE protein is the most likely to be a phosphate factor. Human MEPE can inhibit sodium-dependent phosphorus uptake in renal proximal tubules and human renal cell line (Hu-CL8), showing a dose-dependent manner. Description MEPE protein can affect the reabsorption of urinary phosphate by the kidney. In addition, there are data showing that MEPE is not only significantly increased in hypophosphatemicricket (HYP) and TIO patients, but also is closely related to serum phosphate concentration and parathyroid hormone (PTH) levels in normal human serum. MEPE inhibits bone resorption and mineralization through RGD and aspartate-rich acidic serine-related motifs (ASARM), respectively, and exerts its role in intraosseous balance.

Figure 1. Hypothesis on the mode of action of physiological MEPE and the truncated MEPE proteins in hereditary congenital facial paresis (HCFP) and otosclerosis. (sabelle Schrauwen., et al. 2018)

Relationship between MEPE and Bone and Tooth Calcification

MEPE is considered to be a calcification inhibitor because of the phenomenon of bone hyperplasia and increased bone density during skeletal development of MEPE-/- mice, and the number and viability of osteoblasts are higher than those of wild type mice. In addtion, the osteoblastic cell line of MEPE-/- cultured in vitro was significantly increased in calcification compared with the wild-type osteoblastic cell line. Description MEPE is directly related to bone formation calcification and may inhibit bone calcification. Moreover, the expression of MEPE protein decreased when human dental pulp stem cells differentiated from osteoblasts, suggesting that it inhibits bone calcification.

Other studies have shown that MEPE protein has a function of promoting calcification. Because during the skeletal formation of rats, MEPE/OF45 protein expression can be detected only in osteoblasts with matrix calcification and in bone cells embedded in bone lacuna. The MEPE/OF45 protein was expressed most in mature osteoblasts embedded in the bone lacuna, showing a mature-dependent transient expression. It is indicated that the expression of MEPE protein is highest in rats at the highest peak of calcification. By immunohistochemical analysis, it was found that MEPE protein was mainly expressed in human bone cells, especially in calcified bone cells embedded in bone lacuna. The above data suggest that MEPE protein may have a function of promoting calcification.

Different domains of the MEPE protein have different functions for calcification regulation. On the one hand, an important domain of MEPE protein, ASARM, can inhibit calcification. Studies have shown that cathepsin C can hydrolyze the C-terminus of MEPE protein, and the resulting ASARM fragment has the effect of inhibiting calcification. When the cathepsin C gene mutation causes a functional defect, the ASARM fragment produces less, ectopic calcification or intracranial calcification. On the other hand, another important domain of the MEPE protein, AC-100, promotes calcification. The chemically synthesized MEPE protein RGD and SGDG sequences, namely AC-100, were used to observe the effects of MSCs on pluripotent normal human bone marrow stem cells. It was found that AC-100 can promote the proliferation and differentiation of bone marrow stem cells and promote the formation of calcification spots.

References:

Gullard, A. , Gluhak-Heinrich, J. , Papagerakis, S. , Sohn, P. , Unterbrink, A. , & Chen, S. , et al. (2016). Mepe localization in the craniofacial complex and function in tooth dentin formation. Journal of Histochemistry & Cytochemistry, 64(4), 224-236.
Fujikawa, K. , Yokohamatamaki, T. , Morita, T. , Baba, O. , Qin, C. , & Shibata, S. . (2015). An in situ hybridization study of perlecan, dmp1, and mepe in developing condylar cartilage of the fetal mouse mandible and limb bud cartilage. European Journal of Histochemistry Ejh, 59(3), 211-219.
Isabelle Schrauwen., Hanne Valgaeren., Laura Tomas-Roca., &Hans van Bokhoven., et al. (2018). Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis. Nature, 05 October 2018.

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