
==== Front
CNS Neurosci Ther
CNS Neurosci Ther
10.1111/(ISSN)1755-5949
CNS
CNS Neuroscience & Therapeutics
1755-5930
1755-5949
John Wiley and Sons Inc. Hoboken

39252492
10.1111/cns.70016
CNS70016
CNSNT-2024-1291.R1
Review
Review
Roles of osteocalcin in the central nervous system
Qi et al.
Qi Xiao‐Shan 1 2
He Xin 1
Peng Ying 1
He Xing‐Hong 1
Yang Qian‐Yu 2
Jiao Kai 3
Liu Heng https://orcid.org/0000-0002-6108-5154
1 zmcliuh@163.com

1 Department of Radiology Affiliated Hospital of Zunyi Medical University, Engineering Research Center of Intelligent Medical Imaging in Guizhou Higher Education lnstitutions, Medical Imaging Center of Guizhou Province Zunyi China
2 The First Clinical Medical College Zunyi Medical University Zunyi China
3 State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, School of Stomatology The Fourth Military Medical University Xi‘an China
* Correspondence
Heng Liu, Department of Radiology, Affiliated Hospital of Zunyi Medical University, Engineering Research Center of Intelligent Medical Imaging in Guizhou Higher Education lnstitutions, Medical Imaging Center of Guizhou Province, 149 Dalian Road, Huichuan District, Zunyi, China.
Email: zmcliuh@163.com

09 9 2024
9 2024
30 9 10.1111/cns.v30.9 e7001604 8 2024
27 6 2024
13 8 2024
© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Bone‐derived protein osteocalcin, which has beneficial effects on brain function, may be a future research direction for neurological disorders. A growing body of evidence suggests a link between osteocalcin and neurological disorders, but the exact relationship is contradictory and unclear.

Scope of Review

The aim of this review is to summarize the current research on the interaction between osteocalcin and the central nervous system and to propose some speculative future research directions.

Major Conclusions

In the normal central nervous system, osteocalcin is involved in neuronal structure, neuroprotection, and the regulation of cognition and anxiety. Studies on osteocalcin‐related abnormalities in the central nervous system are divided into animal model studies and human studies, depending on the subject. In humans, the link between osteocalcin and brain function is inconsistent. These conflicting data may be due to methodological inconsistencies. By reviewing the related literature on osteocalcin, some comorbidities of the bone and nervous system and future research directions related to osteocalcin are proposed.

In the normal central nervous system, osteocalcin is involved in neuronal structure, neuroprotection, and the regulation of cognition and anxiety. Studies on osteocalcin‐related abnormalities in the central nervous system are divided into animal model studies and human studies, depending on the subject. In humans, the link between osteocalcin and brain function is inconsistent. These conflicting data may be due to methodological inconsistencies. By reviewing the related literature on osteocalcin, some comorbidities of the bone and nervous system and future research directions related to osteocalcin are proposed.

bone–brain crosstalk
central nervous system
comorbidity
osteocalcin
Young Outstanding Scientific and Technological Talent of Guizhou ProvinceQiankehepingtairencai[2021]5620 Key Basic Research Program of Guizhou ProvinceQiankehejichu‐ZK[2022]zhongdian051 Talent Program for Future Famous Clinical Doctors of Zunyi Medical Universityrc220211205 source-schema-version-number2.0
cover-dateSeptember 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:10.09.2024
Qi X‐S , He X , Peng Y , et al. Roles of osteocalcin in the central nervous system. CNS Neurosci Ther. 2024;30 :e70016. doi:10.1111/cns.70016 39252492
==== Body
pmc1 INTRODUCTION

Osteocalcin, the most abundant noncollagen protein in bone, undeniably plays a role in bone formation and bone loss. 1 , 2 , 3 , 4 A decade ago, uncarboxylated osteocalcin was shown for the first time to cross the blood–brain barrier and bind specifically to neurons to regulate the central nervous system. 5 Thus, a pivotal mouse experiment opened a new era of research on osteocalcin‐mediated regulation of the central nervous system. 5 , 6 , 7

Since then, research into the regulation of osteocalcin has focused on the central nervous system. Since most of the studies are based on animal models and there are differences between human and animal osteocalcin, the evidence from human studies is contradictory and inconsistent. 8 Therefore, it is timely to review the available evidence in light of future studies on the role of osteocalcin in the bone–brain axis. This article reviews the expression and role of osteocalcin in the normal central nervous system and examines the role of osteocalcin in current animal models and human clinical studies. Finally, we discuss the potential limitations of the current research and propose some directions for future research.

2 SYNTHESIS AND RELEASE OF OSTEOCALCIN

This chapter begins with a brief description of how osteocalcin is synthesized and released into the circulation. In humans, the gene that encodes osteocalcin, BGLAP, is located at chromosome 1q25, and its transcription is regulated by vitamin D and Runx2/Cbfa1 (Figure 1). 2 , 9 , 10 , 11 , 12 , 13 The transcribed peptide chains of BGLAP undergo proteolysis followed by vitamin K‐dependent gamma carboxylation at three amino acid residues (glu‐17, ‐21, and ‐24), giving osteocalcin a high affinity for hydroxyapatite and the extracellular matrix. 14 , 15 Since these processes occur more frequently during osteoblast maturation, osteocalcin is also a marker of osteoblast differentiation and maturation. 16 , 17 Through acidification by the extracellular matrix during osteoclastic bone resorption, osteocalcin deposited in the mineralized bone matrix can be decarboxylated and released into extraosseous organs. 18 Moreover, bone resorption affects the decarboxylation of osteocalcin. 19

FIGURE 1 Osteocalcin synthesis and release. The process by which osteocalcin peptides are carboxylated by vitamin K. Two types of osteocalcin can be generated depending on the amount of vitamin K: Carboxylated osteocalcin, which is involved in osteogenesis, and undercarboxylated osteocalcin, which can enter the blood circulation. The decarboxylation of osteocalcin leads to the production of decarboxylated osteocalcin, which can also enter the circulation and participate in acidic bone resorption by osteoclasts. For simplicity, forms of osteocalcin that enter the brain through the blood–brain barrier or placental barrier and thus function in the blood circulation are collectively known as undercarboxylated osteocalcin (with functions similar to uncarboxylated or decarboxylated osteocalcin). Of course, partially intact carboxylated osteocalcin can also be present in the blood circulation, but this is not shown in the figure.

Modeling different forms of osteocalcin via molecular dynamics simulations revealed that the three α‐helices present in the structure form the hydrophobic core of osteocalcin, which has a compact spherical structure as a whole. One of the special structural features of human osteocalcin is the asymmetric distribution of the positive and negative amino acids in the structure, which produces a surface with positive and negative charges on both sides of the protein. Notably, the differences in the structure and kinetics of different forms of osteocalcin may lead to differences in its biological activity. Therefore, future functional studies will quantify the proposed cellular receptor binding affinity and activation with different forms of osteocalcin, which will help elucidate its specific mechanism of action. 14

To facilitate further understanding, current experiments have shown that there are two main functional osteocalcin molecules in the body: carboxylated osteocalcin (mainly involved in osteogenesis) and uncarboxylated or undercarboxylated or decarboxylated osteocalcin (mainly in the blood circulation).

3 ROLE OF OSTEOCALCIN IN THE NORMAL CENTRAL NERVOUS SYSTEM

3.1 Neuronal structure and neuroprotection

Using cell culture models and image analysis, osteocalcin has been shown to promote neurite outgrowth and regulate myelin homeostasis. First, in PC12 cells, both uncarboxylated osteocalcin and carboxylated osteocalcin stimulate NGF‐induced neurite outgrowth; however, this effect is abolished in the absence of osteocalcin. 20 Second, in oligodendrocytes, osteocalcin (OCN) regulates oligodendrocyte differentiation and myelination via G protein‐coupled receptor (GPR) 37 and maintains the balance between myelin production and degradation in the central nervous system. 7 There are two important points related to the OCN/GPR37 axis (Figure 2A). First, Myrf may mediate signaling via the OCN/GPR37 axis. In both in vivo and in vitro studies, exogenous supplementation with osteocalcin reduced the expression of Myrf in a dose‐dependent manner. As GPR37 is not expressed in myelinating Schwann cells, it is an osteocalcin‐specific receptor expressed in mouse oligodendrocytes. 7

FIGURE 2 (A) Osteocalcin regulates myelin homeostasis via GPR37. Osteocalcin regulates myelination in oligodendrocytes and affects the thickness of myelin surrounding neurons. OCN, osteocalcin. (B) Effects of maternal osteocalcin on embryos and adult offspring. Maternal osteocalcin can cross the placental barrier, affect neurogenesis in the embryo, and play a neuroprotective role. Maternal osteocalcin affects learning and memory in adult offspring.

According to studies of different critical periods of biological development, osteocalcin may be linked to the central nervous system. In mice, maternal osteocalcin has been shown to cross the placental and blood–brain barriers, promote neurogenesis, and play a neuroprotective role in the embryonic brain (Figure 2B). The specific evidence that osteocalcin crosses the placental barrier and blood–brain barrier has been excellently reviewed and published. 5 , 21 Generally, maternal osteocalcin accounts for the majority of osteocalcin in the embryo; conversely, a lack of osteocalcin in the embryos of mothers with different maternal phenotypes also leads to varying degrees of neuronal apoptosis. 5 Specifically, on embryonic day 18.5, the embryos of osteocalcin‐deficient (OCN −/− ) mice have twice as many apoptotic cells in the hippocampal region as those of wild‐type mice. 5

3.2 Cognitive function and anxiety

The details of how osteocalcin regulates cognition and anxiety are well summarized, and to avoid repeating the previous review, we briefly summarize the mechanism by which osteocalcin regulates cognition and anxiety. 21 Osteocalcin regulates a variety of neuronal activities related to cognition and anxiety, such as neurotransmitter synthesis, synaptic plasticity, brain‐derived neurotrophic factor synthesis, neurogenesis, and autophagy (Figure 3).

FIGURE 3 There are five mechanisms by which osteocalcin regulates cognition and anxiety. After crossing the blood–brain barrier or placental barrier, osteocalcin is known to bind to specific neurons in the brain through five mechanisms. (A) Osteocalcin regulates neurotransmitter release, increasing monoamine neurotransmitter release and reducing GABA release. (B) Osteocalcin increases synaptic plasticity. (C) OCN/GPR158 promotes the synthesis of RbAp48, leading to increased BDNF release. (D) Osteocalcin promotes neurogenesis. (E) Osteocalcin promotes neuronal autophagy. BDNF, brain‐derived neurotrophic factor; GABA, gamma‐aminobutyric acid; MNs, monoamine neurotransmitters.

In mice, OCN −/− animals exhibit molecular changes in neurotransmitter synthesis compared with littermate wild‐type mice, leading to decreased release of monoamine neurotransmitters (dopamine, norepinephrine, and serotonin) and increased gamma‐aminobutyric acid release via regulation of the gene expression of the enzymes required for synthesis of these neurotransmitters. 5 Genetically, maternal osteocalcin is necessary for spatial learning and hippocampus‐dependent memory in adult offspring because it influences adult hippocampal neurogenesis (Figures 2B and 3). 5 Osteocalcin increases synaptic plasticity and ameliorates age‐related memory loss by regulating GPR158. 6 OCN/GPR158 interacts with the histone‐binding protein RbAp48, which regulates inositol 1,4,5‐trisphosphate and brain‐derived neurotrophic factor expression. 6 , 22 Osteocalcin acts as a direct hormonal inducer of autophagy in hippocampal neurons, 23 ultimately improving hippocampus‐dependent memory and increasing long‐term potentiation. The relationships between osteocalcin and these targets are shown in Figure 3.

4 ROLE OF OSTEOCALCIN IN THE ABNORMAL CENTRAL NERVOUS SYSTEM

In the previous section, osteocalcin was shown to act primarily as a hormone, and its known regulatory functions were reviewed. 24 However, in the body, osteocalcin is more dynamic, especially in disease states, so we will review the role of osteocalcin in neurological disorders.

4.1 The role of osteocalcin in brain function in animal models

At present, there are three animal models of osteocalcin‐related brain dysfunction: cognitive dysfunction, Alzheimer's disease, and Parkinson's disease.

Gu et al. established a rat model of type 2 diabetes mellitus in 2017 with a high‐fat and high‐sugar diet and low‐dose intraperitoneal injection of streptozotocin. 25 A comparison of the cognitive ability of individuals in the low‐level undercarboxylated osteocalcin group and high‐level undercarboxylated osteocalcin group revealed that a decrease in the serum undercarboxylated osteocalcin level was correlated with cognitive impairment. Sedky et al. showed a dose‐dependent improvement in cognitive function in type 2 diabetes mellitus rats after the administration of anti‐diabetic medication. 26 The serum osteocalcin level was significantly increased and correlated with improvements in cognitive dysfunction. Zhao et al. also reported that undercarboxylated osteocalcin improved cognitive dysfunction in a dose‐dependent manner. 27 The rat models of these three studies were all type 2 diabetes mellitus models and had relatively good positive results, but there are still some factors to note: the comprehensiveness of the cognitive assessment methods and the different types of osteocalcin (carboxylated osteocalcin, undercarboxylated osteocalcin, and total osteocalcin). 14

In an Alzheimer's disease mouse model, Shan et al. proposed that osteocalcin ameliorates cognitive impairment in Alzheimer's disease mouse models by reducing the amyloid β burden and upregulating glycolysis in neuroglia. 28 Notably, osteocalcin does not improve glycolysis in neurons but rather in astrocytes and microglia. Furthermore, we investigated whether osteocalcin exerts beneficial effects on Alzheimer's disease by binding to GPR158, GPR37, or other receptors (Figure 4).

FIGURE 4 Schematic showing future directions for research on the role of osteocalcin in the central nervous system. (A) Potential mechanisms of osteocalcin in mice with Alzheimer's disease. (B) Potential mechanisms of OCN/GPR37 in neurodegeneration and neuropsychiatric disorders. (C) Osteocalcin is a potential neuropeptide. During anxiety, OCN‐Cre neurons are activated and play an anti‐anxiety role by promoting the expression of brain‐derived neurotrophic factor and adult hippocampal neurogenesis. AD, Alzheimer's disease; AHN, adult hippocampus neurogenesis; BDNF, brain‐derived neurotrophic factor; OCN, osteocalcin.

Guo et al. improved the behavior disorder of a Parkinson's disease rat model induced by 6‐hydroxydopamine after intraperitoneal injection of exogenous osteocalcin. 29 Osteocalcin was also found to affect glial cells but inhibited the proliferation of astrocytes and microglia. Moreover, this study did not use a GPR158 knockout Parkinson's disease model to determine whether osteocalcin truly exerts its neuroprotective effect through this central receptor in Parkinson's disease rats. According to further research by Hou et al., gut microbiota‐derived propionate mediates the neuroprotective effect of osteocalcin in Parkinson's disease mouse models. 30 However, this study focused more on the protective effect of osteocalcin on Parkinson's disease mice than on its therapeutic effect. Future research may further explore the therapeutic effect of osteocalcin after Parkinson's disease model establishment.

4.2 The association between osteocalcin and brain function in humans

The relationship between blood or cerebrospinal fluid concentrations of osteocalcin and various measures of brain function has been studied in multiple studies in different populations, as summarized in Table 1.

TABLE 1 Association of osteocalcin with brain function in humans.

References	Participant characteristics (men/women)	Measurement of brain function and osteocalcin	Findings	Association of osteocalcin with brain function	
32	n: 225 (108/117)

Age: 74

Health Status: Community dwelling

	Brain function: CANTAB

OCN: CMIA

	Plasma OCN levels were positively associated with measures of executive functioning and global cognition scores in the older women	Positively	
36	n: 44 (21/23)

Age: 50

Health Status: Obese and controls

	Brain function: IGT

tOCN: ELISA

	Lower tOCN associated with higher IGT scores	Positively	
34	n: 196 men

Age: 56

Health Status: T2DM

	Brain function: RBANS

uOCN: ELISA

	Serum uOCN was positively correlated with RBANS scores	Positively	
38	n: 103 (15/88)

Age: 80

Health Status: Community dwelling

	Brain function: 19 cognitive function tests

uOCN & cOCN: ELISA

tOCN: ECLIA

	No significant association between tOCN and uOCN and the rate of cognition change	No correlation	
33	n: 42 PM women

Age: 58

Health Status: Community dwelling

	Brain function: CANTAB

tOCN & uOCN: RIA

	Serum uOCN predicted tasks associated with reaction time and executive function	No correlation	
41	n: 95 (47/48)

Age: 62

Health Status: T2DM

	Brain function: PSS

cOCN: ELISA

	Higher cOCN associated with higher PSS scores	Negatively	
35	n: 82 men

Age: 70

Health Status: Early‐stage AD and controls

	Brain function: MoCA, MMSE

tOCN: RIA

	Higher tOCN associated with lower MoCA scores	Negatively	
No association between tOCN and MMSE scores	No correlation	
31	n: 800 (90/710)

Age: 76

Health Status: Community dwelling

	Brain function: MMSE

uOCN: measured

by BML Inc.

	Higher uOCN associated with impaired orientation, calculation and language	Negatively	
42	n: 38 (8/30)

Age: 57

Health Status: PHPT

	Brain function: STAI‐S; BDI

tOCN: RIA & ELISA

	Lower tOCN associated with higher BDI and STAI‐S scores	Positively	
39	n: 790 (87/703)

Age: 76

Health Status: Community dwelling

	Brain function: GDS

uOCN: measured

by BML Inc.

	Higher uOCN associated with higher risk of depression	Negatively	
40	n: 13 women

Age: 50

Health Status: Depression

	Brain function: MADRS

uOCN: CAEIA

	Lower uOCN associated with reduced depressive symptoms	Negatively	
43	n: 158 (77/81)

Age: Full‐term born

Health Status: Vaginal births infants

	Brain function: WPPSI‐III, ASQ‐III, MABC‐2, SDQ

tOCN: the iSYS technique

	Higher serum OCN at 4 months of age associated with higher intelligence quotient and better motor control at 4 years	Positively	
Higher cord OCN associated with poorer processing speed and fine motor control at 4 years of age	Negatively	
37	n: 208 women

Age: 49

Health Status: HIV infection and demographically similar HIV

	Brain function: NP

uOCN: ELISA

	Higher uOCN associated with higher executive function in the total sample and in WLWH.	Positively	
Higher uOCN associated with higher motor skills in WLWH	Positively	
Higher uOCN associated with poorer attention/working memory in the total sample	Negatively	
44	n: 120 (28/92)

Age: 73

Health Status: POD and non‐POD

	Brain function: CAM, DRS

tOCN & uOCN: ELISA

	Preoperative higher uOCN in CSF associated with a higher incidence of delirium and with greater severity of delirium	Negatively	
Note: Association of osteocalcin with brain function outcomes – positively, higher osteocalcin associated with beneficial brain function; negatively, higher osteocalcin associated with detrimental brain function; no correlation, no correlation between osteocalcin and brain function.

Abbreviations: AD, Alzheimer's disease; ASQ‐III, the Ages & Stages Questionnaire, Third Edition; BDI, the beck depression inventory; CAEIA, commercially available enzyme immunoassay; CAM, the confusion assessment method; CANTB, the Cambridge Neurological Test Automated Battery; CMIA, commercial multiplex immunoassays; cOCN, carboxylated osteocalcin; DRS, the delirium rating scale‐98; ECLIA, electrochemiluminescence immunoassay; ELISA, enzyme‐linked immunosorbent assay; GDS, Japanese version of the 15‐item Geriatric Depression Scale; IGT, Iowa Gambling Task; MABC‐2, the Movement Assessment Battery for Children, Second Edition; MADRS, the Montgomery Asberg Depression Rating Scale; MMSE, mini mental state examination; MoCA, Montreal Cognitive Assessment; NP, neuropsychological test battery; OCN, osteocalcin; PHPT, primary hyperparathyroidism; PM, post‐menopausal; POD, postoperative delirium group; PSS, perceived stress scale; RBANS, the repeatable battery for the assessment of neuropsychological status; RIA, radioimmunoassay; SDQ, the Strengths and Difficulties Questionnaire; STAI‐S, State–Trait Anxiety Inventory‐State; T2DM, type 2 diabetes mellitus; tOCN, total osteocalcin; uOCN, undercarboxylated osteocalcin; WPPSI‐III, Wechsler Preschool and Primary Scale of Intelligence, Third Edition.

Eight studies examining the relationship between changes in osteocalcin blood concentrations and cognitive function were identified. 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 Six studies showed a single relationship, three showed a positive association, one showed a negative association, and two showed no association between high serum osteocalcin concentrations and cognitive function (Table 1). 31 , 32 , 33 , 34 , 36 , 38 A study of 800 elderly people in a community in Tokyo, Japan, reported that higher serum undercarboxylated osteocalcin concentrations were associated with impaired orientation, calculation, and language, that is, a negative correlation with brain function. 31 The remaining two studies show more than one relationship. Pu et al. reported that high total osteocalcin was associated with lower montreal cognitive assessment scores but not mini mental state examination scores on cognitive tests in early‐stage men with Alzheimer's disease. 35 In addition, Ross et al. reported differences in the association between cognitive scores and high undercarboxylated osteocalcin in human immunodeficiency virus‐infected patients and controls. 37

Four studies reported an association between serum osteocalcin concentrations and depressive symptoms in patients. 39 , 40 , 41 , 42 One of the studies on primary hyperparathyroidism showed a positive correlation, reporting that low levels of osteocalcin were associated with poorer mental performance. 42 Three other studies reported negative associations, two of which showed that elevated serum undercarboxylated osteocalcin levels were associated with an increased risk of depression. 39 , 40 , 41

One study correlated serum osteocalcin with future neurodevelopment. 43 Berggren et al. investigated the relationship between total serum osteocalcin levels and neurodevelopment at age 4 in 158 healthy full‐term vaginal infants. 43 That is, increased serum osteocalcin levels at 4 months were associated with increased intelligence quotient and motor control at 4 years of age. In contrast, higher umbilical osteocalcin was associated with poorer processing speed and fine motor control at 4 years of age. Moreover, a recent study showed that high preoperative cerebrospinal fluid uncarboxylated osteocalcin concentrations were associated with the incidence and severity of postoperative delirium. 44

There are many possible explanations for the inconsistent findings of previous studies of human osteocalcin and brain function. First, the methods used for measuring osteocalcin differ to some extent. Therefore, the use of standardized and reliable assays to report circulating concentrations of specific forms of osteocalcin is recommended in human studies. 45 , 46 , 47 Different forms of osteocalcin are involved in different physiological processes on the body. 5 , 14 Therefore, it is not clear whether the ratio of osteocalcin is better than that of osteocalcin alone in reflecting the circulating concentration of patients. 48 In previous clinical studies, the osteocalcin ratio has been shown to be a good predictor of bone loss and fracture risk. 49 , 50 Second, in some of the included studies, there were no reports that participants in the study might have used vitamin K, vitamin D, corticosteroids, exercise, or other factors known to affect circulating undercarboxylated osteocalcin levels. 2 , 51 , 52 , 53 Finally, the included studies recruited participants from different populations, including healthy individuals, patients of different age groups, individuals with diabetes, individuals with obesity, and individuals with other medical conditions. These risk factors have been reported to affect the serum osteocalcin concentration and may lead to inconsistent results. 48 , 54 , 55 Overall, animal studies seem to indicate a protective effect of osteocalcin on central nervous system disease, which seems to contradict findings from some human biomarker studies. This may also be due to differences in osteocalcin between animals and humans. 8 The nervous system can affect bone metabolism, and the positive association between high circulating osteocalcin and central nervous system disease in humans may be due to reverse causality. 56 , 57 Mendelian randomization studies may address the causal role of osteocalcin in central nervous system disease. 58 , 59

5 RECOMMENDATIONS FOR FUTURE RESEARCH

5.1 Bone and nervous system comorbidities

Osteocalcin is one of the mediators of bone and central nervous system communication. At the same time, by reviewing the literature, we found that some bone‐brain comorbidities are related to the mechanisms by which osteocalcin regulates brain function. Therefore, we will introduce the research on osteoporosis, multiple sclerosis, and cerebral palsy, and the potential association with osteocalcin to provide more breakthrough ideas for future research.

5.1.1 Osteoporosis

Osteoporosis is a chronic systemic bone disease characterized by a decrease in bone mineral density and deterioration of bone microstructure and is accompanied by various neurological deficits such as cognitive impairment, anxiety, and depression. 60 , 61 , 62 As osteocalcin is an important component of bone loss and bone formation, exploring the role of osteocalcin in osteoporosis, a systemic disease, will greatly promote our understanding of the physiology and pathology of the body.

Three observational studies are worth mentioning. 63 , 64 , 65 First, patients with cognitive decline have an increased risk of bone loss and fracture. 63 In contrast, another prospective study showed an improvement in memory in patients with cognitive decline after fracture rehabilitation. 65 Although the association between osteocalcin and cognitive function was not mentioned in the above clinical studies, osteocalcin levels were significantly increased in patients with osteoporosis and Alzheimer's disease. 64 These findings suggest that osteoporosis and Alzheimer's disease may have a common pathogenesis and that osteocalcin is involved in this pathogenesis. Of note, however, due to the presence of impaired bone formation per se in patients with osteoporosis, the use of other markers of bone turnover, in addition to the determination of different forms of osteocalcin, was suggested during the study.

5.1.2 Multiple sclerosis

Multiple sclerosis is a chronic demyelinating disease characterized by intermittent episodes of focal inflammation and neurological dysfunction. 66 Patients with multiple sclerosis are often complicated by bone loss, cognitive impairment, and depression. 67 When these diseases occur together, they strongly affect daily activities and quality of life.

There are many potential links between osteocalcin and multiple sclerosis changes in the nervous system. First, brain‐derived neurotrophic factors play a neuroprotective role in multiple sclerosis. 68 Radiographically, white matter damage in multiple sclerosis patients is associated with cognitive impairment. 69 , 70 Exercise training is a promising treatment for multiple sclerosis‐related cognitive impairment. 71 Osteocalcin not only regulates brain function but also increases muscle mass and promotes exercise recovery. 7 , 72 Since only osteocalcin responds to bone formation in patients and there is no direct evidence linking changes in the nervous system to multiple sclerosis, future research could therefore begin by exploring the effects of osteocalcin on the nervous system in multiple sclerosis animal models.

5.1.3 Cerebral palsy

Cerebral palsy is an umbrella term that encompasses a group of disorders characterized by impaired walking and is attributed to nonprogressive dysfunction of fetal and infant brain development. 73 Dyskinesia in children with cerebral palsy is usually associated with neurological dysfunction and secondary musculoskeletal problems, and musculoskeletal interactions affect motor ability in children with cerebral palsy. 74 People with cerebral palsy also experience bone loss due to impaired weight bearing, and the risk of fractures is even greater. 75 Due to developmental delay and damage to various biological systems, people with cerebral palsy develop neurological disorders, including cognitive impairment, depression and anxiety, and pain, in childhood or early adulthood. 76 , 77 , 78

Many of the mechanisms by which osteocalcin regulates neural function are also involved in cerebral palsy. First, in the transcriptional biomarkers of cerebral palsy, dysregulation of nutrient signaling pathways, such as brain‐derived neurotrophic factor pathways, is responsible for the decrease in neuronal protection. 79 In terms of the molecular etiology of cerebral palsy, most patients have myelin dysfunction and abnormal lipid metabolism. 80 In addition to regulating brain function, osteocalcin can also improve lipid metabolism. 81 Second, enhancing the plasticity of children with cerebral palsy is beneficial for their rehabilitation. 82 In a mouse model of cerebral palsy, modulation of the autophagy pathway prevents neuroinflammation and neuronal death. 83 Different investigators have demonstrated that osteocalcin regulates the autophagy pathway. 23 , 84 Therefore, osteocalcin may have a promising future in further elucidating the etiology of abnormalities in different systems involved in cerebral palsy, such as the nervous and skeletal muscle systems.

5.2 Other future directions

5.2.1 Myelin and OCN/GPR37

Myelin alterations and the OCN/GPR37 signaling pathway may be two good targets for further elucidating the osteocalcin‐related pathological progression of different neurological diseases (Figure 4A). First, Alzheimer's disease model mice exhibited increased myelin thickness similar to that observed in OCN −/− mice. 7 , 85 Recent studies in mice have shown that enhanced myelin turnover reverses cognitive impairment in Alzheimer's disease. 86 Thus, studying aberrant changes in OCN −/− mice may contribute to elucidating the pathological progression of comorbidities of bone and the central nervous system, or to further understanding other mechanisms by which osteocalcin regulates cognition. Second, GPR37 has different functions in different neurological diseases. 87 , 88 Overexpression of the GPR37 receptor in Parkinson's disease stimulates autophagy in neurons. 87 GPR37 is also overexpressed in neuropsychiatric diseases. 88 Since osteocalcin regulates autophagy and anxiety‐like behavior, exploring the OCN/GPR37 signaling pathway is important for understanding the pathophysiological processes of neurological disorders (Figure 4B).

5.2.2 A potential neuropeptide

We investigated whether osteocalcin plays other roles in the nervous system in addition to being an osteogenic hormone, such as by acting as a neuropeptide (Figure 4C). Researchers found reduced sensory responses in OCN −/− mice, suggesting that osteocalcin may act as a neuropeptide. 89 , 90 Moreover, immunoreactive neurons were found in both peripheral and central nerves. 91 , 92 , 93 , 94 Interestingly, a recent study on anxiety in OCN‐Cre mice showed that OCN‐Cre+ cells in the outer layer of the dorsal dentate gyrus of the hippocampus are selectively activated to exert anxiolytic effects upon exposure to an external anxiety‐inducing stimulus. 95 OCN‐Cre transgenic mice were generated by gene knockout technology using the human osteocalcin gene promoter (see “Materials and Methods” in the literature). 96 Although the above study suggested that osteocalcin may be a potential neuropeptide, it should be ruled out that osteocalcin is a marker of only neurons. Both studies showed that osteocalcin‐knockout mice had hypoesthesia, but the hypoesthesia in one of the studies may be due to myelin alterations. 7 , 89 Therefore, whether osteocalcin functions as a neuropeptide needs to be explored carefully.

6 CONCLUSION

After the synthesis of osteocalcin, due to the different carboxylation conditions, mainly uncarboxylated osteocalcin, undercarboxylated osteocalcin and decarboxylated osteocalcin are present in the circulation. The main functions of osteocalcin in the central nervous system include its involvement in neural structure and neuroprotection and its regulation of cognition and anxiety. In diseases of the central nervous system, good positive results have been obtained in animal studies, i.e., osteocalcin improves cognitive function. In some human studies, high osteocalcin has been associated with improved brain function (i.e., cognitive function, depression, neurodevelopment). However, there have been some different findings in human studies, such as some studies linking high osteocalcin with deterioration of brain function. One explanation for this is reverse causality, in which high levels of osteocalcin in patients with brain dysfunction may be a response to the disease rather than a cause. At the same time, osteocalcin, a member of the bone‐brain axis, is speculated to play a promising role in exploring the pathogenesis of bone‐nervous system comorbidities. In addition, the mechanisms related to the regulation of brain function by osteocalcin, multiple sclerosis, and cerebral palsy were clarified. Future research directions for osteocalcin in the regulation of brain function, namely, myelin changes and the OCN/GPR37 signaling pathway, are suggested, and osteocalcin may be a potential neuropeptide.

AUTHOR CONTRIBUTIONS

X.S.Q. wrote the first draft of the manuscript. X.S.Q., X.H., Y.P., X.H.H., Q.Y.Y., K.J., and H.L. contributed to writing, correction, and addition of fundamental insights to the manuscript. H.L. and K.J. conceived the presented idea, organized the structure of the review, and took the lead in writing the manuscript. All authors read and approved the final version of the manuscript.

FUNDING INFORMATION

This work was supported by the Young Outstanding Scientific and Technological Talent of Guizhou Province (grant No. Qiankehepingtairencai[2021]5620), Key Basic Research Program of Guizhou Province (grant No. Qiankehejichu‐ZK[2022]zhongdian051), and Talent Program for Future Famous Clinical Doctors of Zunyi Medical University (rc220211205).

CONFLICT OF INTEREST STATEMENT

All authors state that they have no competing interests.

ACKNOWLEDGMENTS

Not applicable.

DATA AVAILABILITY STATEMENT

Not applicable.
==== Refs
REFERENCES

1 Bailey S , Poundarik AA , Sroga GE , Vashishth D . Structural role of osteocalcin and its modification in bone fracture. Appl Phys Rev. 2023;10 (1 ):11410.
2 Hauschka PV , Lian JB , Cole DE , Gundberg CM . Osteocalcin and matrix Gla protein: vitamin K‐dependent proteins in bone. Physiol Rev. 1989;69 (3 ):990‐1047.2664828
3 Ivaska KK , Hentunen TA , Vääräniemi J , Ylipahkala H , Pettersson K , Väänänen HK . Release of intact and fragmented osteocalcin molecules from bone matrix during bone resorption in vitro. J Biol Chem. 2004;279 (18 ):18361‐18369.14970229
4 Power MJ , Fottrell PF . Osteocalcin: diagnostic methods and clinical applications. Crit Rev Clin Lab Sci. 1991;28 (4 ):287‐335.1930680
5 Oury F , Khrimian L , Denny CA , et al. Maternal and offspring pools of osteocalcin influence brain development and functions. Cell. 2013;155 (1 ):228‐241.24074871
6 Khrimian L , Obri A , Ramos‐Brossier M , et al. Gpr158 mediates osteocalcin's regulation of cognition. J Exp Med. 2017;214 (10 ):2859‐2873.28851741
7 Qian Z , Li H , Yang H , et al. Osteocalcin attenuates oligodendrocyte differentiation and myelination via GPR37 signaling in the mouse brain. Sci Adv. 2021;7 (43 ):eabi5811.34678058
8 Al Rifai O , Julien C , Lacombe J , et al. The half‐life of the bone‐derived hormone osteocalcin is regulated through O‐glycosylation in mice, but not in humans. Elife. 2020;9 :e61174.33284103
9 Ducy P , Zhang R , Geoffroy V , Ridall AL , Karsenty G . Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. 1997;89 (5 ):747‐754.9182762
10 Kerner SA , Scott RA , Pike JW . Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3. Proc Natl Acad Sci U S A. 1989;86 (12 ):4455‐4459.2786632
11 Paredes R , Arriagada G , Cruzat F , et al. Bone‐specific transcription factor Runx2 interacts with the 1alpha,25‐dihydroxyvitamin D3 receptor to up‐regulate rat osteocalcin gene expression in osteoblastic cells. Mol Cell Biol. 2004;24 (20 ):8847‐8861.15456860
12 Puchacz E , Lian JB , Stein GS , Wozney J , Huebner K , Croce C . Chromosomal localization of the human osteocalcin gene. Endocrinology. 1989;124 (5 ):2648‐2650.2785029
13 Zaidi SK , Javed A , Choi JY , et al. A specific targeting signal directs Runx2/Cbfa1 to subnuclear domains and contributes to transactivation of the osteocalcin gene. J Cell Sci. 2001;114 (Pt 17 ):3093‐3102.11590236
14 Kapoor K , Pi M , Nishimoto SK , Quarles LD , Baudry J , Smith JC . The carboxylation status of osteocalcin has important consequences for its structure and dynamics. Biochim Biophys Acta Gen Subj. 2021;1865 (3 ):129809.33340588
15 Poser JW , Esch FS , Ling NC , Price PA . Isolation and sequence of the vitamin K‐dependent protein from human bone. Undercarboxylation of the first glutamic acid residue. J Biol Chem. 1980;255 (18 ):8685‐8691.6967872
16 Bellows CG , Reimers SM , Heersche JN . Expression of mRNAs for type‐I collagen, bone sialoprotein, osteocalcin, and osteopontin at different stages of osteoblastic differentiation and their regulation by 1,25 dihydroxyvitamin D3. Cell Tissue Res. 1999;297 (2 ):249‐259.10470495
17 Owen TA , Aronow M , Shalhoub V , et al. Progressive development of the rat osteoblast phenotype in vitro: reciprocal relationships in expression of genes associated with osteoblast proliferation and differentiation during formation of the bone extracellular matrix. J Cell Physiol. 1990;143 (3 ):420‐430.1694181
18 Ferron M , Wei J , Yoshizawa T , et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142 (2 ):296‐308.20655470
19 Ducy P . The role of osteocalcin in the endocrine cross‐talk between bone remodelling and energy metabolism. Diabetologia. 2011;54 (6 ):1291‐1297.21503740
20 Ando E , Higashi S , Mizokami A , Watanabe S , Hirata M , Takeuchi H . Osteocalcin promotes proliferation, differentiation, and survival of PC12 cells. Biochem Biophys Res Commun. 2021;557 :174‐179.33865226
21 Obri A , Khrimian L , Karsenty G , Oury F . Osteocalcin in the brain: from embryonic development to age‐related decline in cognition. Nat Rev Endocrinol. 2018;14 (3 ):174‐182.29376523
22 Kosmidis S , Polyzos A , Harvey L , et al. RbAp48 protein is a critical component of GPR158/OCN signaling and ameliorates age‐related memory loss. Cell Rep. 2018;25 (4 ):959‐973.30355501
23 Glatigny M , Moriceau S , Rivagorda M , et al. Autophagy is required for memory formation and reverses age‐related memory decline. Curr Biol. 2019;29 (3 ):435‐448.30661803
24 Karsenty G . The facts of the matter: what is a hormone? PLoS Genet. 2020;16 (6 ):e1008938.32589668
25 Gu PY , Yu F , Jin S , et al. Analysis of serum undercarboxylated osteocalcin level in rats with type 2 diabetes mellitus and the correlation with cognitive impairment. Exp Ther Med. 2017;14 (3 ):2603‐2607.28962201
26 Sedky AA . Improvement of cognitive function, glucose and lipid homeostasis and serum osteocalcin levels by liraglutide in diabetic rats. Fundam Clin Pharmacol. 2021;35 (6 ):989‐1003.33683755
27 Zhao Y , Yang L , Chen M , et al. Study on Undercarboxylated Osteocalcin in improving cognitive function of rats with type 2 diabetes mellitus by regulating PI3K‐AKT‐GSK/3β signaling Pathwaythrough medical images. Biotechnol Genet Eng Rev. 2023b;10 :1‐16.
28 Shan C , Zhang D , Ma DN , et al. Osteocalcin ameliorates cognitive dysfunctions in a mouse model of Alzheimer's disease by reducing amyloid β burden and upregulating glycolysis in neuroglia. Cell Death Dis. 2023;9 (1 ):46.
29 Guo XZ , Shan C , Hou YF , et al. Osteocalcin ameliorates motor dysfunction in a 6‐Hydroxydopamine‐induced Parkinson's disease rat model through AKT/GSK3β signaling. Front Mol Neurosci. 2018;11 :343.30319352
30 Hou YF , Shan C , Zhuang SY , et al. Gut microbiota‐derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson's disease. Microbiome. 2021;9 (1 ):34.33517890
31 Azuma K , Osuka Y , Kojima N , Sasai H , Kim H , Inoue S . Association of Vitamin K insufficiency with cognitive dysfunction in community‐dwelling older adults. Front Nutr. 2021;8 :811831.35174198
32 Bradburn S , McPhee JS , Bagley L , et al. Association between osteocalcin and cognitive performance in healthy older adults. Age Ageing. 2016;45 (6 ):844‐849.27515675
33 Castle M , Fiedler N , Pop LC , et al. Three doses of vitamin D and cognitive outcomes in older women: a double‐blind randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2020;75 (5 ):835‐842.30951148
34 Fang H , Xu XY , Xu RZ , Zhen YF , Xu G , Li YK . Decreased serum undercarboxylated osteocalcin is associated with cognitive impairment in male patients with type 2 diabetes. J Diabetes Complications. 2018;32 (1 ):56‐60.29126874
35 Pu Z , Tang X , Fei Y , et al. Bone metabolic biomarkers and bone mineral density in male patients with early‐stage Alzheimer's disease. Eur Geriatr Med. 2020;11 (3 ):403‐408.32297255
36 Puig J , Blasco G , Daunis‐i‐Estadella J , et al. Lower serum osteocalcin concentrations are associated with brain microstructural changes and worse cognitive performance. Clin Endocrinol (Oxf). 2016;84 (5 ):756‐763.26406918
37 Ross RD , Olali AZ , Shi Q , et al. Brief report: Undercarboxylated Osteocalcin is associated with cognition in women with and without HIV. J Acquir Immune Defic Syndr. 2022;91 (2 ):162‐167.36094482
38 Ross RD , Shah RC , Leurgans S , Bottiglieri T , Wilson RS , Sumner DR . Circulating Dkk1 and TRAIL are associated with cognitive decline in community‐dwelling, older adults with cognitive concerns. J Gerontol A Biol Sci Med Sci. 2018;73 (12 ):1688‐1694.
39 Azuma K , Osuka Y , Kojima N , Sasai H , Kim H , Inoue S . Association of Vitamin K insufficiency as evaluated by serum undercarboxylated osteocalcin with depressive symptoms in community‐dwelling older adults. Am J Geriatr Psychiatry. 2022;30 (9 ):1051‐1052.35641403
40 Bartečků E , Hořínková J , Křenek P , et al. Osteocalcin levels decrease during the treatment of an acute depressive episode. Front Psych. 2022;13 :893012.
41 Nguyen MM , Anita NZ , Darwish L , et al. Serum osteocalcin is associated with subjective stress in people with depression and type 2 diabetes. Psychoneuroendocrinology. 2020;122 :104878.33038647
42 Wang SM , He Y , Zhu MT , et al. The associations of serum Osteocalcin and cortisol levels with the psychological performance in primary hyperparathyroidism patients. Front Endocrinol. 2021;12 :692722.
43 Berggren S , Andersson O , Hellström‐Westas L , Dahlgren J , Roswall J . Serum osteocalcin levels at 4 months of age were associated with neurodevelopment at 4 years of age in term‐born children. Acta Paediatr. 2022;111 (2 ):338‐345.34647329
44 Mi Y , Wen O , Lei Z , Ge L , Xing L , Xi H . Insulin resistance and osteocalcin associate with the incidence and severity of postoperative delirium in elderly patients undergoing joint replacement. Geriatr Gerontol Int. 2024;24 (4 ):421‐429.38438300
45 Bhadricha H , Khatkhatay MI , Desai M . Development of an in house ELISA for human intact osteocalcin and its utility in diagnosis and management of osteoporosis. Clin Chim Acta. 2019;489 :117‐123.30537473
46 Bi H , Bian P , Gopinath SCB , Marimuthu K , Lv G , Yin XH . Identifying mineral decrement with bone injury by quantifying osteocalcin on current‐volt sensor. Biotechnol Appl Biochem. 2022;69 (5 ):2061‐2068.34622990
47 Inal Kabala S , Yagar H , Ozcan HM . A new biosensor for osteoporosis detection. Prep Biochem Biotechnol. 2019;49 (5 ):511‐520.30888246
48 Smith C , Voisin S , Al Saedi A , et al. Osteocalcin and its forms across the lifespan in adult men. Bone. 2020;130 :115085.31622778
49 Luukinen H , Käkönen SM , Pettersson K , et al. Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin. J Bone Miner Res. 2000;15 (12 ):2473‐2478.11127212
50 Smith C , Lewis JR , Sim M , et al. Higher Undercarboxylated to Total Osteocalcin ratio is associated with reduced physical function and increased 15‐year falls‐related hospitalizations: the Perth longitudinal study of aging women. J Bone Miner Res. 2021;36 (3 ):523‐530.33615560
51 Hiam D , Landen S , Jacques M , et al. Osteocalcin and its forms respond similarly to exercise in males and females. Bone. 2021;144 :115818.33338665
52 Je SH , Joo NS , Choi BH , et al. Vitamin K supplement along with vitamin D and calcium reduced serum concentration of undercarboxylated osteocalcin while increasing bone mineral density in Korean postmenopausal women over sixty‐years‐old. J Korean Med Sci. 2011;26 (8 ):1093‐1098.21860562
53 Wald JA , Jusko WJ . Corticosteroid pharmacodynamic modeling: osteocalcin suppression by prednisolone. Pharm Res. 1992;9 (8 ):1096‐1098.1409384
54 Aoki A , Muneyuki T , Yoshida M , et al. Circulating osteocalcin is increased in early‐stage diabetes. Diabetes Res Clin Pract. 2011;92 (2 ):181‐186.21292339
55 Bador KM , Wee LD , Halim SA , et al. Serum osteocalcin in subjects with metabolic syndrome and central obesity. Diabetes Metab Syndr. 2016;10 (1 Suppl 1 ):S42‐S45.26482049
56 Dimitri P , Rosen C . The central nervous system and bone metabolism: an evolving story. Calcif Tissue Int. 2017;100 (5 ):476‐485.27501818
57 Elefteriou F . Impact of the autonomic nervous system on the skeleton. Physiol Rev. 2018;98 (3 ):1083‐1112.29717928
58 Liu W , Hu Q , Zhang F , Shi K , Wu J . Investigation of the causal relationship between osteocalcin and dementia: a Mendelian randomization study. Heliyon. 2023;9 (10 ):e21073.37916108
59 Skrivankova VW , Richmond RC , Woolf BAR , et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE‐MR Statement. JAMA. 2021;326 (16 ):1614‐1621.34698778
60 Compston JE , McClung MR , Leslie WD . Osteoporosis. Lancet. 2019;393 (10169 ):364‐376.30696576
61 Kashfi SS , Abdollahi G , Hassanzadeh J , Mokarami H , Khani Jeihooni A . The relationship between osteoporosis and depression. Sci Rep. 2022;12 (1 ):11177.35778459
62 Zhao Y , Chen H , Qiu F , He J , Chen J . Cognitive impairment and risks of osteoporosis: a systematic review and meta‐analysis. Arch Gerontol Geriatr. 2023a;106 :104879.36462246
63 Bliuc D , Tran T , Adachi JD , et al. Cognitive decline is associated with an accelerated rate of bone loss and increased fracture risk in women: a prospective study from the Canadian multicentre osteoporosis study. J Bone Miner Res. 2021;36 (11 ):2106‐2115.34289172
64 Luckhaus C , Mahabadi B , Grass‐Kapanke B , et al. Blood biomarkers of osteoporosis in mild cognitive impairment and Alzheimer's disease. J Neural Transm (Vienna). 2009;116 (7 ):905‐911.19468818
65 Mitsuboshi N , Kouzuki M , Kobayashi Y , et al. Post‐fracture rehabilitation effects on brain function in older people. Yonago Acta Med. 2019;62 (1 ):62‐66.30962746
66 Jakimovski D , Bittner S , Zivadinov R , et al. Multiple sclerosis. Lancet. 2024;403 (10422 ):183‐202.37949093
67 Lo LMP , Taylor BV , Winzenberg T , Palmer AJ , Blizzard L , van der Mei I . Change and onset‐type differences in the prevalence of comorbidities in people with multiple sclerosis. J Neurol. 2021;268 (2 ):602‐612.32880720
68 Linker RA , Lee DH , Demir S , et al. Functional role of brain‐derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. Brain. 2010;133 (Pt 8 ):2248‐2263.20826430
69 Abel S , Vavasour I , Lee LE , et al. Associations between findings from myelin water imaging and cognitive performance among individuals with multiple sclerosis. JAMA Netw Open. 2020;3 (9 ):e2014220.32990740
70 Eijlers AJC , Meijer KA , van Geest Q , Geurts JJG , Schoonheim MM . Determinants of cognitive impairment in patients with multiple sclerosis with and without atrophy. Radiology. 2018;288 (2 ):544‐551.29786489
71 DeLuca J , Chiaravalloti ND , Sandroff BM . Treatment and management of cognitive dysfunction in patients with multiple sclerosis. Nat Rev Neurol. 2020;16 (6 ):319‐332.32372033
72 Mera P , Laue K , Ferron M , et al. Osteocalcin signaling in Myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab. 2016;23 (6 ):1078‐1092.27304508
73 Bekteshi S , Monbaliu E , McIntyre S , et al. Towards functional improvement of motor disorders associated with cerebral palsy. Lancet Neurol. 2023;22 (3 ):229‐243.36657477
74 Modlesky CM , Zhang C . Complicated muscle‐bone interactions in children with cerebral palsy. Curr Osteoporos Rep. 2020;18 (1 ):47‐56.32060718
75 Whitney DG , Alford AI , Devlin MJ , Caird MS , Hurvitz EA , Peterson MD . Adults with cerebral palsy have higher prevalence of fracture compared with adults without cerebral palsy independent of osteoporosis and Cardiometabolic diseases. J Bone Miner Res. 2019;34 (7 ):1240‐1247.30730595
76 Fluss J , Lidzba K . Cognitive and academic profiles in children with cerebral palsy: a narrative review. Ann Phys Rehabil Med. 2020;63 (5 ):447‐456.32087307
77 Ng TKS , Tagawa A , Ho RC , et al. Commonalities in biomarkers and phenotypes between mild cognitive impairment and cerebral palsy: a pilot exploratory study. Aging. 2021;13 (2 ):1773‐1816.33497355
78 Smith KJ , Peterson MD , O'Connell NE , et al. Risk of depression and anxiety in adults with cerebral palsy. JAMA Neurol. 2019;76 (3 ):294‐300.30592485
79 Alpay Savasan Z , Kim SK , Oh KJ , Graham SF . Advances in cerebral palsy biomarkers. Adv Clin Chem. 2021;100 :139‐169.33453864
80 Li N , Zhou P , Tang H , et al. In‐depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy. Brain. 2022;145 (1 ):119‐141.34077496
81 Zhang XL , Wang YN , Ma LY , Liu ZS , Ye F , Yang JH . Uncarboxylated osteocalcin ameliorates hepatic glucose and lipid metabolism in KKAy mice via activating insulin signaling pathway. Acta Pharmacol Sin. 2020;41 (3 ):383‐393.31659239
82 Reid LB , Rose SE , Boyd RN . Rehabilitation and neuroplasticity in children with unilateral cerebral palsy. Nat Rev Neurol. 2015;11 (7 ):390‐400.26077839
83 Srivastava IN , Shperdheja J , Baybis M , Ferguson T , Crino PB . mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy. Neurobiol Dis. 2016;85 :144‐154.26459113
84 Zhou B , Li H , Liu J , et al. Autophagic dysfunction is improved by intermittent administration of osteocalcin in obese mice. Int J Obes (Lond). 2016;40 (5 ):833‐843.26740123
85 Wu Y , Ma Y , Liu Z , Geng Q , Chen Z , Zhang Y . Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer's disease mouse model. Neurosci Lett. 2017;642 :102‐106.28174059
86 Chen JF , Liu K , Hu B , et al. Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer's disease. Neuron. 2021;109 (14 ):2292‐2307.34102111
87 Marazziti D , Di Pietro C , Golini E , et al. Induction of macroautophagy by overexpression of the Parkinson's disease‐associated GPR37 receptor. FASEB J. 2009;23 (6 ):1978‐1987.19218498
88 Tomita H , Ziegler ME , Kim HB , et al. G protein‐linked signaling pathways in bipolar and major depressive disorders. Front Genet. 2013;4 :297.24391664
89 Patterson‐Buckendahl P , Shahid M , Shah A , Pohorecky LA . Altered ethanol consumption in Osteocalcin null mutant mice. Cell Mol Neurobiol. 2018;38 (1 ):261‐271.28852891
90 Patterson‐Buckendahl P , Sowinska A , Yee S , et al. Decreased sensory responses in osteocalcin null mutant mice imply neuropeptide function. Cell Mol Neurobiol. 2012;32 (5 ):879‐889.22350212
91 Ichikawa H , Itota T , Torii Y , Inoue K , Sugimoto T . Osteocalcin‐immunoreactive primary sensory neurons in the rat spinal and trigeminal nervous systems. Brain Res. 1999;838 (1–2 ):205‐209.10446334
92 Ichikawa H , Jin HW , Fujita M , Nagaoka N , Sugimoto T . Osteocalcin‐immunoreactive neurons in the vagal and glossopharyngeal sensory ganglia of the rat. Brain Res. 2005;1031 (1 ):129‐133.15621021
93 Ichikawa H , Sugimoto T . The difference of osteocalcin‐immunoreactive neurons in the rat dorsal root and trigeminal ganglia: co‐expression with nociceptive transducers and central projection. Brain Res. 2002;958 (2 ):459‐462.12470885
94 Suzuki T , Sato T , Ichikawa H . Osteocalcin‐ and osteopontin‐containing neurons in the rat hind brain. Cell Mol Neurobiol. 2012;32 (8 ):1265‐1273.22552891
95 Sun D , Milibari L , Pan JX , et al. Critical roles of embryonic born dorsal dentate granule neurons for activity‐dependent increases in BDNF, adult hippocampal neurogenesis, and antianxiety‐like behaviors. Biol Psychiatry. 2021;89 (6 ):600‐614.33183762
96 Zhang M , Xuan S , Bouxsein ML , et al. Osteoblast‐specific knockout of the insulin‐like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem. 2002;277 (46 ):44005‐44012.12215457
