Proprotein convertase furin regulates osteocalcin and bone endocrine function

Rifai, Omar Al; Chow, Jacqueline; Lacombe, Julie; Julien, Catherine; Faubert, Denis; Susan‐Resiga, Delia; Essalmani, Rachid; Creemers, John W.M.; Seidah, Nabil G.; Ferron, Mathieu

doi:10.1172/jci93437

Cited by 59 publications

(62 citation statements)

References 58 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Could we prevent and control obesity in humans by targeting bone? In addition to LCN2, additional bone‐secreted factors may be involved in regulating food intake, as deletion of furin , the pro‐protein convertase responsible for pro‐OCN cleavage and maturation, in osteoblasts reduced food intake in a LCN2‐independent manner . This study further reinforces the involvement of bone in appetite control, opening up new avenues of research with potential future therapeutic applications.…”

Section: Osteoblast‐derived Lcn2 As An Appetite Suppressorsupporting

confidence: 69%

“…The implication of bone resorption in glucose homeostasis has also been examined . Moreover, evidence indicates the involvement of the osteoclast differentiation factor receptor activator of nuclear factor κ‐B ligand (RANKL), neuropeptide Y (NPY), and other unidentified bone‐derived factors in maintaining glucose homeostasis. In the current review, we summarize recent advances in our understanding of the role of the skeleton in modulating glucose metabolism and the possibilities arising for treating, preventing and predicting diabetes by bone intervention.…”

Section: Introductionmentioning

confidence: 99%

“…factor κ-B ligand (RANKL), 16 neuropeptide Y (NPY), 17 and other unidentified bone-derived factors [18][19][20] in maintaining glucose homeostasis. In the current review, we summarize recent advances in our understanding of the role of the skeleton in modulating glucose metabolism and the possibilities arising for treating, preventing and predicting diabetes by bone intervention.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Bone: Another potential target to treat, prevent and predict diabetes

Liu¹,

Mosialou

Liu

2018

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.

show abstract

Section: Osteoblast‐derived Lcn2 As An Appetite Suppressorsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Bone: Another potential target to treat, prevent and predict diabetes

Liu¹,

Mosialou

Liu

2018

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

show abstract

“…Intriguinly, the increased insulin sensitivity in Phospho1 -/mice was not associated with the 318 expected rise in serum GLU13-OCN levels suggesting that PHOSPHO1-regulated energy metabolism is via OCN-319 independent mechanisms. This notion has previously been observed when partial genetic ablation of osteoblasts 320 profoundly affected energy expenditure, gonadal fat weight and insulin sensitivity which were not restored by the 321 administration of OCN (19,20). Nevertheless, it is possible that the increased insulin sensitivity noted in the Phospho1 -322 /mice may be primed by an initial rise in GLU13-OCN levels, which is eventually normalized in a compensatory 323 manner by the observed increase in Esp expression.…”

Section: Discussion 311mentioning

confidence: 87%

PHOSPHO1, a novel skeletal regulator of insulin resistance and obesity

Suchacki

Morton

Vary

et al. 2020

Preprint

View full text Add to dashboard Cite

26The skeleton is recognised as a key endocrine regulator of metabolism. Here we show that mice lacking the bone 27 mineralization enzyme PHOSPHO1 (Phospho1 -/-) exhibited improved basal glucose homeostasis and resisted high-fat-28 diet induced weight gain and diabetes. The metabolic protection in Phospho1 -/mice was manifested in the absence of 29 altered levels of osteocalcin. Osteoblasts isolated from Phospho1 -/mice were enriched for genes associated with 30 energy metabolism and diabetes; Phospho1 both directly and indirectly interacted with genes associated with glucose 31 transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the 32 metabolic protection observed in adult Phospho1 -/mice. However, the decreased serum choline levels in Phospho1 -/-33 mice were normalized by feeding a 2% choline rich diet resulting in a normalization in insulin sensitivity and fat mass. 34This study identifies PHOSPHO1 as a potential therapeutic target for the treatment of obesity and diabetes.In addition to its classical structural functions, the skeleton is a site of significant glucose uptake and is involved in the 66 regulation of whole-body glucose metabolism (1-8). Osteocalcin (OCN) is the most abundant osteoblast-specific non-67 collagenous protein derived from bone and is thought to maintain the mechanical properties of the bone matrix by 68 regulating calcium binding when fully carboxylated (GLA13-OCN) (9). However, when OCN is not γ-carboxylated 69 (uncarboxylated (GLU-OCN) or undercarboxylated (GLU13-OCN)), it is released from bone into the circulation where 70 it is able to regulate whole-body glucose metabolism in an endocrine manner (7,(10)(11)(12)(13). Mice deficient in OCN have 71 increased fat mass and are hyperglycemic, hypoinsulinemic and insulin-resistant in muscle. Furthermore, serum GLU17-72 OCN (human form of GLU13) levels and β-cell function show an inverse correlation with glycated haemoglobin 73 (HbA1c), fat mass and plasma glucose levels (14-18). 74 75Osteoblasts regulate glucose metabolism through OCN-dependent and independent mechanisms (19,20).An 76 alternative candidate is the bone-specific cytosolic phosphatase; Phosphatase, Orphan 1 (PHOSPHO1) (21)(22)(23)(24)(25)(26)(27)(28)(29)(30). 77 PHOSPHO1 initiates bone matrix mineralization and PHOSPHO1 deficiency causes significant skeletal pathology, 78 bowed long bones, osteomalacia and scoliosis in early life (31)(32)(33)(34). In addition to the role of PHOSPHO1 in skeletal 79 biomineralization, PHOSPHO1 has been implicated in the regulation of energy metabolism in humans (35)(36)(37)(38). Within 80 the PHOSPHO1 gene, differential methylation sites have been identified as potentially useful biomarkers for clinical 81 application in the early detection of type-2 diabetes (35) and significant associations between methylation at loci within 82 the PHOSPHO1 gene and the future risk of type-2 diabetes exist (36,37). Differential methylation in PHOSPHO1 was 83 associated with three lipid traits (tota...

show abstract

“…TGFβ1 and PDGF are known to play roles both in osteogenic differentiation and angiogenesis [103][104][105]. Qi et al also found that hiPSC-MSC-Exo induced high expression of osteopontin, osteocalcin, and type I collagen (COL1), and enhanced bone mineralization [84,106]. Meanwhile, high expression of phosphorylated protein and bone matrix acidic protein (DMP1) was found in the extracellular matrix (ECM) containing MSCs-Exo, suggesting MSCs-Exo promotes calcium phosphate recruitment and bone mineralization [107].…”

Section: Key Protein Factors Carried By Exosomes Regulate Bone Regenementioning

confidence: 99%

Potential Therapeutic Applications of Exosomes in Bone Regenerative Medicine

Yang¹,

Zhu²,

Lu³

et al. 2019

Osteogenesis and Bone Regeneration

View full text Add to dashboard Cite

The ability of bone regeneration is relatively robust, which is crucial for fracture healing, but delayed healing and nonunion are still common problems in clinical practice. Fortunately, exciting results have been achieved for regenerative medicine in recent years, especially in the area of stem cell-based treatment, but all these cell-based approaches face challenging problems, including immune rejection. For this reason, exosomes, stem cell-derived small vesicles of endocytic origin, have attracted the attention of many investigators in the field of bone regeneration. One of the attractive features of exosomes is that they are small and can travel between cells and deliver bioactive products, including miRNA, mRNA, proteins, and various other factors, to promote bone regeneration, with undetectable immune rejection. In this chapter, we intend to briefly update the recent progressions, and discuss the potential challenges in the target areas. Hopefully, our discussion would be helpful not only for the clinicians and the researchers in the specific disciplines but also for the general audiences as well.

show abstract

Proprotein convertase furin regulates osteocalcin and bone endocrine function

Cited by 59 publications

References 58 publications

Bone: Another potential target to treat, prevent and predict diabetes

Bone: Another potential target to treat, prevent and predict diabetes

PHOSPHO1, a novel skeletal regulator of insulin resistance and obesity

Potential Therapeutic Applications of Exosomes in Bone Regenerative Medicine

Contact Info

Product

Resources

About