Osteocalcin, ovarian senescence, and brain health
Introduction
Menopausal transition is a natural phenomenon leading into reproductive senescence. Menopause is defined retrospectively by the time of the final menstrual period, followed by 1 year of amenorrhea; peri-menopause refers to the transition to menopause that occurs slowly over about a 10 year period (Butler and Santoro, 2011). Most women transition from a reproductively active to a reproductively quiescent phase without much harm; however, a substantial proportion of women emerge from this transition with an increased risk of neurological decline (Brinton, 2015). Menopausal transition is known to significantly increase a woman’s risk of Alzheimer’s disease (AD), vascular dementia (VD), cardiac arrest, and stroke (Harlow, 2012, Mosconi, 2018, Lisabeth and Bushnell, 2012). Similar to AD and VD, cognitive decline remains a significant consequence of stroke and cardiac arrest, further limiting recovery and survival (Stephens, 2004, Levine, 2015, Barba, 2000, Tatemichi, 1993). The average age of menopausal transition is around 51 years of age, and the age at which menopausal transition occurs is a determinant of risk and incidence of these diseases. For example, occurrence of natural menopause before age 42 years doubles the stroke risk (Lisabeth, 2009, Baba, 2010). Earlier age at menopause has also been found to predict faster cognitive decline due to sharper declines in concentrations of circulating estradiol and estrone (Trevoux, 1986, Bove, 2014, Ryan, 2014).
The decline in estrogens during menopause also accelerates bone remodeling, with a net increase in bone resorption leading to bone loss and in severe cases osteoporosis (Seeman and Martin, 2019). On average, women can lose up to 25% of their trabecular bone mass and up to 15% of cortical bone in the first 10 years after menopause (Sowers, 2003). Premature ovarian failure or any long phases in which a woman has low sex hormone levels and infrequent or absent menstrual periods can also reduce bone mass. This decline translates clinically as 40% of menopausal women suffer some type of fracture because of frailty (Sowers, 2003).
Frailty is characterized by an increased vulnerability to acute stressors and the reduced capacity of various bodily systems secondary to age-associated physiological deterioration (Xue, 2011). Pre-frailty -- the critical window of time between non-frail and frail -- is the period most amenable to intervention and, in some cases, prevention. In a woman’s life, the pre-frailty period is considered peri-menopause, when multiple estrogen-regulated systems (including thermoregulation, sleep, circadian rhythms, and sensory processing) and domains of cognitive function can be disrupted (Brinton, 2015). Disruption in cognition also predicts the onset of physical frailty (Gross, 2016). Frailty further worsens the effects of menopause as frail menopausal women likely suffer more devastating neurological conditions like stroke or cardiac arrest leading to cerebral ischemia (Lisabeth and Bushnell, 2012, Garcia, 2016). Interventions during pre-frailty may also mitigate the risk of subsequent age-related neurological diseases, reduce cognitive decline, and improve overall quality of life after stroke/cardiac arrest. Women generally outlive men and survive for 80+ years and are likely to spend 30+ years with postmenopausal morbidity.
The aforementioned evidence suggests that physical and cognitive well-being go hand-in-hand and are linked. Physical exercise (PE) and the PE mimetic low frequency whole body vibration (WBV) are powerful behavioral interventions that reduce frailty and improve health outcomes in elderly stroke/cardiac arrest survivors. Low frequency vibration reduces or reverses pathological remodeling of bone and reduces frailty-related physiological deterioration (Bramlett, 2014, Rubin, 2001, Xie et al., 2008). In a separate study, post-stroke WBV intervention greatly reduced inflammation and infarct volume while significantly increasing brain-derived neurotrophic factor and improvement in functional activity in middle-aged female rats (Raval, 2018). These studies emphasize how interventions that target the physiological factors underlying frailty can mitigate menopause-related frailty. Physical frailty can include sarcopenia/myopenia, osteoporosis, and declined physical activity. The question arises as to whether physical frailty could be reduced by increasing physical activity, thereby conferring improved muscle and bone health. Muscle and bone are known to release myokines and the bone-derived hormone osteocalcin, respectively. Could the bone-derived hormone osteocalcin (OCN) mediate interventions to mitigate menopause-related frailty? In this direction, a recent study suggests that ischemic stroke patients with better outcomes had higher serum OCN levels than those whose National Institutes of Health Stroke Scale (NIHSS) scores did not improve (Wu, 2020). Studies from different laboratories suggest that OCN plays a key role in the regulation of bone and energy metabolism and also impacts age-related cognition (Shan, 2019, Karsenty, 2017, Khrimian et al., 2017, Khrimian, 2017, Kosmidis, 2018). As such, OCN could modulate the physiological drivers of frailty in menopausal women and is therefore the focus of this review.
Section snippets
What is osteocalcin (OCN)?
Osteocalcin is the tenth most abundant protein in vertebrates (Lee, 2007). Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid and 5.6 kD) non-collagenous protein. Osteocalcin is produced predominately by osteoblasts, but small amounts are also produced by odontoblasts of the teeth and hypertrophic chondrocytes (Karsenty, 2017). Osteoblasts are found in the metabolically active portions of bone including the periosteum and endosteum
What are the hormonal effects of OCN?
Studies in rodents suggest that in serum, ucOCN regulates glucose metabolism in several tissues including skeletal muscle, bone, pancreatic islet β cells, and Leydig cells of the testes (Mizokami et al., 2017, Lacombe, 2020). The effects of ucOCN on these tissues were shown to increase energy metabolism and are mediated by the G protein-coupled receptor family C group 6 member A (GPRC6A) along with other indirect molecular pathways which have been well described in previous reviews (Karsenty,
What are the effects of estrogens on OCN?
In a laboratory study using rat osteoblasts, estrogen receptor activation increases osteoblast proliferation and OCN production (Wang, 2014). Furthermore, studies found that when combined with shear mechanical stress, E2 synergistically increases the proliferation of osteoblasts and the expression of mRNA coding for OCN (Deepak et al., 2017, Li, 2017). The mechanism of action of shear stress on bone is known to act through calcium signaling leading to prostaglandin E2 (PGE2) and nitric oxide
What are the effects of menopause on bone and OCN?
Slow decline in circulating estrogens at the menopausal transition leads to osteoporosis (Stepan et al., 2019, Riggs et al., 1998). Osteoporosis is a disease in which the density and quality of bone are reduced, resulting in brittle, porous bone. Similar to the menopause transition, the process of osteoporosis occurs silently and progressively leading to imbalance between the complementary activities of osteoclasts and osteoblasts required for normal bone formation. According to a considerable
What are the possible explanations for observed discrepancies in circulating OCN levels?
Measurement of precise OCN concentrations has proven to be challenging. Common limitations to measuring serum OCN levels in many previous studies includes differences in laboratory measurement, ability to detect intact vs. fragmented OCN, and differences in physiologic state, which may alter measured serum OCN. Currently, the three most common ways to quantify OCN are immunoradiometric assay, radioimmune assay, and enzyme-linked immunosorbent assay. Laboratory protocols often use monoclonal or
What is the compelling evidence that suggests the role of OCN in the CNS?
Using an in vitro model of ischemia in neuronal culture, the study from Wu et al (2020) shows that OCN promotes neuronal survival by downregulating proline hydroxylase 1; osteocalcin leads glucose metabolism to the pentose phosphate pathway and therefore inhibits pyroptosis (Wu, 2020). It was also shown that acute ischemic patients with better outcomes had higher serum OCN levels than those whose NIH Stroke Scale (NIHSS) scores did not improve; therefore, this study proposes that osteocalcin
Why OCN instead of estradiol-17β replacement in reproductively senescent females to enhance cognition?
The estrogen family includes the hormones estrone, estradiol (17β-estradiol; E2) and estriol, all of which were shown to influence brain functions. Most of the studies investigating the role of estrogen on brain, however, have used E2, as it is the most potent of estrogens. E2 mediates its effect on the brain via estrogen receptors (ERs), which are abundant in the areas of the brain controlling memory and executive cognitive function. ER isoforms are differentially expressed within the brain,
Will reducing menopause-associated physical frailty also reduce cognitive frailty?
It is now clear that decline and impairment in cognition predicts the onset of physical frailty and vice versa. Therapeutic interventions to reduce frailty should also target both components since menopause transition is associated with neurological (hot flashes, night sweats, dysphoric mood, sleep disturbance, depression, and dementia) and physical (osteoporosis, osteoarthritis) morbidity. This is of added importance as menopausal transition has been shown to make a woman more susceptible to
Summary
Although the skeletal system is routinely viewed as metabolically inert with a solely mechanical function, data presented in this review suggest that the metabolic processes of the skeletal system can significantly influence cognition. Specifically, multiple studies cited in this review clearly support a role of the bone-derived hormone osteocalcin (OCN) to reduce anxiety and cognitive deficits via its receptor and RbAp48-mediated increased BDNF levels in the brain (Karsenty, 2017, Kosmidis,
Acknowledgments
We would like to thank Dr. Micheline McCarthy, Professor of Neurology at the University of Miami for the critical review of our manuscript. This work was supported by an Endowment from Drs. Chantal and Peritz Scheinberg (Ami P. Raval), Florida Department of Heath # 7JK01 (Helen M. Bramlett & Ami P. Raval), and # 20K09 funds (Ami P. Raval), and The Miami Project to Cure Paralysis (Helen M. Bramlett) and the National Institutes of Health(NIH)/National Institute of Neurological Disorders and Stroke
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