DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease

Dussold, Corey; Gerber, Claire; White, Samantha A.; Wang, Xueyan; Qi, Lixin; Francis, CM; Capella, Maralee; Courbon, Guillaume; Wang, Jingya; Li, Chaoyuan; Feng, Jian Q.; Isakova, Tamara; Wolf, Myles; David, Véronique; Martin, Aline

doi:10.1038/s41413-019-0051-1

Cited by 67 publications

(99 citation statements)

References 48 publications

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“…and remodeling of the matrix present inside the local microenvironment (Gluhak-Heinrich et al, 2003). In addition, DMP1 also inhibits the apoptosis of osteocytes, enhances bone mineralization, and prevents the disintegration of the osteocyte network (Dussold et al, 2019). MEPE is synchronized with DMP1 and differentially regulates bone remodeling by mechanical loading.…”

Section: Regulation Of Osteocytes By the Ecmmentioning

confidence: 99%

The Bone Extracellular Matrix in Bone Formation and Regeneration

et al. 2020

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Bone regeneration repairs bone tissue lost due to trauma, fractures, and tumors, or absent due to congenital disorders. The extracellular matrix (ECM) is an intricate dynamic bio-environment with precisely regulated mechanical and biochemical properties. In bone, ECMs are involved in regulating cell adhesion, proliferation, and responses to growth factors, differentiation, and ultimately, the functional characteristics of the mature bone. Bone ECM can induce the production of new bone by osteoblast-lineage cells, such as MSCs, osteoblasts, and osteocytes and the absorption of bone by osteoclasts. With the rapid development of bone regenerative medicine, the osteoinductive, osteoconductive, and osteogenic potential of ECM-based scaffolds has attracted increasing attention. ECM-based scaffolds for bone tissue engineering can be divided into two types, that is, ECM-modified biomaterial scaffold and decellularized ECM scaffold. Tissue engineering strategies that utilize the functional ECM are superior at guiding the formation of specific tissues at the implantation site. In this review, we provide an overview of the function of various types of bone ECMs in bone tissue and their regulation roles in the behaviors of osteoblast-lineage cells and osteoclasts. We also summarize the application of bone ECM in bone repair and regeneration. A better understanding of the role of bone ECM in guiding cellular behavior and tissue function is essential for its future applications in bone repair and regenerative medicine.

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Section: Regulation Of Osteocytes By the Ecmmentioning

confidence: 99%

The Bone Extracellular Matrix in Bone Formation and Regeneration

et al. 2020

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“…Osteocytes produce various signaling proteins such as sclerostin, WNT1, WNT3a, Dickkopf-related protein 1 (DKK1), phosphate regulating endopeptidase homolog X-linked (PHEX), RANKL, MEPE, fibroblast growth factor-23 (FGF23), sclerostin, and vascular endothelial growth factor (VEGF) ( 31 – 34 ). These proteins and growth factors not only play a crucial role in bone biology, but also in other organs such as kidney, and in fat metabolism ( 34 , 35 ). Disruption of the production of these proteins by impaired osteocyte function causes bone diseases, including rare bone diseases ( 36 – 40 ).…”

Section: Introductionmentioning

confidence: 99%

“…The osteocyte is a critical player in chronic kidney disease-associated adverse effects on bone and heart ( 76 ). Osteocyte-derived DMP1 reduces FGF23 expression and enhances bone mineralization ( 35 ). Chronic kidney disease reduces DMP1 expression in osteocytes, while DMP1 supplementation prevents osteocyte apoptosis, lowers FGF23 expression, increases serum phosphate, and prevents the development of left ventricular hypertrophy in a chronic kidney disease mice model ( 35 , 76 ).…”

Section: Introductionmentioning

confidence: 99%

“…Osteocyte-derived DMP1 reduces FGF23 expression and enhances bone mineralization ( 35 ). Chronic kidney disease reduces DMP1 expression in osteocytes, while DMP1 supplementation prevents osteocyte apoptosis, lowers FGF23 expression, increases serum phosphate, and prevents the development of left ventricular hypertrophy in a chronic kidney disease mice model ( 35 , 76 ). PHEX indirectly regulates FGF23, and PHEX gene mutation causes hypophosphatemic rickets, a rare hereditary bone disease ( 39 ).…”

Section: Introductionmentioning

confidence: 99%

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The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

2020

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Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.

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“…In particular, osteoblast arrangement is a direct contributor to the oriented construction of the bone matrix [ 14 , 15 ]. Impaired bone cell activities are linked to various bone diseases [ 16 , 17 ]. For example, inflammatory conditions are associated with osteoporosis and increased risk of fractures [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Role of Interleukin-6 as a Regulatory Factor of Inflammation-Associated Deterioration in Osteoblast Arrangement

Matsugaki

Matsumoto

Nakano

2020

IJMS

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Inflammatory disorders are associated with bone destruction; that is, deterioration in bone cell activities are under the control of the innate immune system. Macrophages play a central role in innate immunity by switching their polarized phenotype. A disturbed immune system causes aberrance in the ordered bone matrix microarrangement, which is a dominant determinant of bone tissue functionalization. However, the precise relationship between the immune system and bone tissue organization is unknown. In this study, the controlled in vitro co-culture assay results showed that M1-polarized macrophages disrupted the osteoblast alignment, which directly modulate the oriented bone matrix organization, by secreting pro-inflammatory cytokines. Notably, interleukin-6 was found to be a key regulator of unidirectional osteoblast alignment. Our results demonstrated that inflammatory diseases triggered bone dysfunction by regulating the molecular interaction between the immune system and bone tissue organization. These findings may contribute to the development of therapeutic targets for inflammatory disorders, including rheumatoid arthritis.

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DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease

Cited by 67 publications

References 48 publications

The Bone Extracellular Matrix in Bone Formation and Regeneration

The Bone Extracellular Matrix in Bone Formation and Regeneration

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

A Novel Role of Interleukin-6 as a Regulatory Factor of Inflammation-Associated Deterioration in Osteoblast Arrangement

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