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

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

doi:10.1038/s41413-019-0051-1

Corey Dussold, Aline Martin + Show 13 more

Open Access

https://doi.org/10.1038/s41413-019-0051-1

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Abstract

During chronic kidney disease (CKD), alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality. The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization, but its effects in CKD are unknown. We tested the hypothesis that DMP1 supplementation in CKD would improve bone health, prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes. We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3−/− mouse model of CKD. Col4a3−/− mice demonstrated impaired kidney function, reduced bone DMP1 expression, reduced bone mass, altered osteocyte morphology and connectivity, increased osteocyte apoptosis, increased serum FGF23, hyperphosphatemia, left ventricular hypertrophy (LVH), and reduced survival. Genetic or pharmacological supplementation of DMP1 in Col4a3−/− mice prevented osteocyte apoptosis, preserved osteocyte networks, corrected bone mass, partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription, and further increased serum phosphate. Despite impaired kidney function and worsened hyperphosphatemia, DMP1 prevented development of LVH and improved Col4a3−/− survival. Our data suggest that CKD reduces DMP1 expression, whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.

Highlights

Chronic kidney disease (CKD), which affects over 10% of the population worldwide, causes progressive loss of kidney function and significant alterations in mineral and bone metabolism
Elevated fibroblast growth factor 23 (FGF23) in CKD is independently associated with cardiovascular disease and all-cause mortality,[7,8,9,10] and is thought to contribute mechanistically to development of left ventricular hypertrophy (LVH), which is an important precursor of heart failure in patients with CKD.[11,12,13,14,15]
We demonstrate that CKD leads to significant alterations in osteocytes, including apoptosis, reduced dentin matrix protein 1 (DMP1) expression and activation of the calcium-dependent NFAT signaling that contributes to increased FGF23 transcription

Summary

INTRODUCTION

Chronic kidney disease (CKD), which affects over 10% of the population worldwide, causes progressive loss of kidney function and significant alterations in mineral and bone metabolism These include loss of bone mass, increased susceptibility to fractures, and increased levels of circulating fibroblast growth factor 23 (FGF23).[1,2] FGF23 is a phosphate- and vitamin D-regulating hormone produced and secreted by osteocytes. We studied Col4a3−/− mice that recapitulate many features of human CKD including progressive loss of kidney function, alterations of bone and mineral metabolism, elevations of circulating FGF23 levels, development of LVH in slow progressing B6 Col4a3−/−, and shortened lifespan.[29,30,31,32] We demonstrate that CKD leads to significant alterations in osteocytes, including apoptosis, reduced DMP1 expression and activation of the calcium-dependent NFAT signaling that contributes to increased FGF23 transcription. Using genetic and pharmacologic approaches to increase DMP1 concentrations in bone of WT and Col4a3−/− mice with CKD, we show that restoration of DMP1 in bone prevents CKDassociated bone disease by reducing osteocyte apoptosis, lowers FGF23 production via an NFAT signaling pathway, attenuates LVH, and prolongs survival despite unchanged severity of kidney disease and worsened hyperphosphatemia

RESULTS

DMP1TG

DISCUSSION

MATERIALS AND METHODS