Breaking News
February 16, 2019 - Conformance of genetic characteristics found to be crucial for longer preservation of kidney graft
February 16, 2019 - Researchers use optogenetic tool to control, visualize receptor signals in neural cells
February 16, 2019 - New reversible antiplatelet therapy could reduce risk of blood clots, prevent cancer metastasis
February 16, 2019 - Testosterone is not the only hormone needed for penis development
February 16, 2019 - FDA Advisory Committee Recommends Approval of Spravato (esketamine) Nasal Spray for Adults with Treatment-Resistant Depression
February 15, 2019 - Heart surgery technology developed at Baptist Health debuts after years of secrecy
February 15, 2019 - Prescription Opioids Double Risk of Triggering Fatal Car Crash
February 15, 2019 - New study helps doctors better understand high blood pressure in pregnant women
February 15, 2019 - Beta wave control in Parkinson’s diseased brain could be a potential therapy
February 15, 2019 - Media representations of love may justify gender-based violence in young people
February 15, 2019 - Yoga May Help With Rheumatoid Arthritis Symptoms, Severity
February 15, 2019 - Obstructive sleep apnea linked to inflammation, organ dysfunction
February 15, 2019 - Master your mind: A challenge from WELL for Life
February 15, 2019 - Why Some Brain Tumors Respond to Immunotherapy
February 15, 2019 - Must-Reads Of The Week From Brianna Labuskes
February 15, 2019 - Researchers uncover novel mechanism and potential new therapeutic target for Alzheimer’s
February 15, 2019 - Genetic variations in a fourth gene associated with higher ALL risk in Hispanic children
February 15, 2019 - Disruptive behavioral problems in kindergarten linked with lower employment earnings in adulthood
February 15, 2019 - New bioengineered device enhances the production of T-cells
February 15, 2019 - HDL proteome behaves like a tiny Velcro ball that is rolling on surfaces
February 15, 2019 - Puerto Rican children more likely to have poor or decreasing use of asthma inhalers
February 15, 2019 - Quality of patient care does not improve after physician-hospital integration
February 15, 2019 - Synopsys release new software for implant design and patient-specific planning
February 15, 2019 - 6 out of 10 hip replacements last 25 years or longer
February 15, 2019 - Health Tip: What You Should Know About Antibiotics
February 15, 2019 - New research challenges medical consensus that adenoids and tonsils significantly shrink during teenage years
February 15, 2019 - Discovery of weakness in a rare cancer could be exploited with drugs
February 15, 2019 - UVA scientists find potential explanation for mysterious cell death in Alzheimer’s, Parkinson’s
February 15, 2019 - New rules requiring female athletes to lower testosterone levels are based on flawed data
February 15, 2019 - Researchers comprehensively sequence the human immune system
February 15, 2019 - Researchers study animal venoms to identify new medicines for treating diseases
February 15, 2019 - Movement of wrist bones revealed by MRI and computer modeling
February 15, 2019 - Philips introduces new premium digital X-ray room to help shorten patient wait times
February 15, 2019 - Women fare worse than men following aortic heart surgery, study finds
February 15, 2019 - High-protein and low-calorie diet helps older adults lose weight safely, shows study
February 15, 2019 - Drug microdosing effects may not measure up to big expectations
February 15, 2019 - Discharged, Dismissed: ERs Often Miss Chance To Set Overdose Survivors On ‘Better Path’
February 15, 2019 - A digitized lab environment to be showcased at smartLAB 2019
February 15, 2019 - Scientists uncover main mechanisms of fluconazole drug resistance
February 15, 2019 - New study seeks to understand how colibactin causes cancer
February 15, 2019 - Photoacoustic imaging accurately measures the temperature of deep tissues
February 15, 2019 - Large study finds no association between phthalate exposure and breast cancer risk
February 15, 2019 - New research explains presence of ‘natural’ magnetism in human cells
February 15, 2019 - Bio-Rad launches new digital PCR system and kit for monitoring treatment response in CML patients
February 15, 2019 - Excessive daytime sleepiness in OSA patients linked to greater risk for cardiovascular diseases
February 15, 2019 - Scientists shed light on damaging cell effects linked to aging
February 15, 2019 - Celiac disease may be caused by stomach bug in childhood
February 15, 2019 - NHS performance figures highlight the true scale of Emergency Department crisis
February 15, 2019 - High intensity exercise may improve health by increasing gut microbiota diversity
February 15, 2019 - Apellis’ APL-2 Receives Orphan Drug Designation from the FDA for the Treatment of Autoimmune Hemolytic Anemia
February 15, 2019 - Couples creating art or playing board games release ‘love hormone’
February 15, 2019 - Glimpsing The Future At Gargantuan Health Tech Showcase
February 15, 2019 - Common herbicide found to increase the risk of lymphoma
February 15, 2019 - Over-abundance of energy to cells could increase cancer risk
February 15, 2019 - Oxford Genetics appoints Jocelyne Bath as new Chief Operating Officer
February 15, 2019 - Castration-resistant metastatic prostate cancer responds to combination of immune checkpoint inhibitors
February 15, 2019 - Large-scale clinical trial begins to study liver transplantation between people with HIV
February 15, 2019 - Cannabis use among adolescents linked with increased risk of depression in adulthood
February 15, 2019 - Fractures, head injuries common in electric scooter accidents, UCLA study finds
February 15, 2019 - Prenatal maternal depression has important consequences for infant temperament, study shows
February 15, 2019 - Stereotactic body radiotherapy effective in treating men with low- or intermediate-risk prostate cancer
February 15, 2019 - Zogenix Submits New Drug Application to U.S. Food & Drug Administration for Fintepla for the Treatment of Dravet Syndrome
February 15, 2019 - Certain birthmarks warrant quick treatment, pediatricians say
February 15, 2019 - New machine learning method predicts if atypical ductal hyperplasia will turn cancerous
February 15, 2019 - Whole-genome sequencing and sharing real-time data could limit spread of foodborne bacteria
February 15, 2019 - FDA warns doctor for illegally marketing unapproved implantable device
February 15, 2019 - New injury documentation tool may provide better evidence for elder abuse cases
February 15, 2019 - Physiological age is a better predictor of survival than chronological age, shows study
February 15, 2019 - New study reveals high success rate for hip and knee replacements
February 15, 2019 - Prenatal exposures to BPA may pose threat to human ovarian function
February 15, 2019 - Suspicious spots on the lungs of children with rhabdomyosarcoma do not behave like metastases
February 15, 2019 - Diet drinks daily could raise stroke risk says study
February 15, 2019 - Many Systematic Reviews Do Not Fully Report Adverse Events
February 15, 2019 - Seven tips to protect your child from burns
February 15, 2019 - Keynote speakers announced for CBD Expo MIDWEST
February 15, 2019 - New DNA methylation GrimAge tool allows you to predict lifespan and healthspan
February 15, 2019 - New AI-driven platform analyze how pathogens infect human cells
February 15, 2019 - Increased activity of EHMT2 gene deficient neurons could cause autism in humans
February 15, 2019 - Recurring UTIs may mask symptoms of bladder or kidney cancer
February 15, 2019 - Researchers conduct extensive comparison of drugs used in treating neuroendocrine tumors
The role of the alkaline phosphatase (Alpl) gene in preventing premature bone ageing

The role of the alkaline phosphatase (Alpl) gene in preventing premature bone ageing

image_pdfDownload PDFimage_print
The expression of Alpl decreased in the bone marrow with age. a) Representative image of immunostaining showing Alpl (green) in the bone marrow (BM) of 2-month old mice, b-c) ALP activities in serum and TNSALP expression levels in the bone marrow of young (2-month) and old (24-month) mice analyzed with ALP activity assay and Western blotting showed decreased protein expression with age, d) Immunohistochemical analysis of TNSALP (brown) of the femoral diaphysis, e) Quantified area of TNSALP+ decreased with age. Credit: Bone Research, doi: 10.1038/s41413-018-0029

Mutations of the alkaline phosphatase (ALPL) gene in the liver, bone and kidney can cause hypophosphatasia (HPP) and early-onset bone dysplasia, asserting its key role in human bone development. Despite its importance, its mechanism of action during bone ageing is largely unknown. In a recent study published in Bone Research, Wenjia Liu and co-workers at the Xi’an Institute of Tissue Engineering and Regenerative Medicine demonstrated that the knockdown of ALPL gene induced premature bone ageing characteristics, including bone mass loss and marrow fat gain. The phenomenon was coupled with impaired mesenchymal stem cell (MSC) differentiation. The scientists then reactivated the pathway using the diabetes drug metformin to restore the ability of stem cells to grow and differentiate into bone-producing osteoblasts and prevent bone ageing.

The MSCs are precursors of bone producing osteoblasts and the protein encoded by the ALPL gene is enriched in the stem cell membrane, with involvement in ATP metabolism during cell differentiation. Liu et al. determined the mechanism of bone ageing with loss-of-function studies, where ALPL deficiency in stem cells enhanced the release of ATP, while reducing its hydrolysis to cause extracellular ATP boost. The ATP when internalized by MSCs inactivated the AMPKα cell signaling pathway (master regulator of cellular energy homeostasis), contributing to MSC cell fate switch by impairing their ability to grow and proliferate. The work was conducted in vitro and in a mutant mouse model (Alpl+/) exhibiting premature ageing, followed by metformin treatment to improve the function of endogenous MSCs by reactivating the cell signaling pathway.

Alkaline phosphatase (ALP) was initially identified in 1912 as a ubiquitous ectoenzyme widely distributed in nature from bacteria to humans. ALP is a well-known osteoblastic marker used as a diagnostic index to detect the bone forming capacity in osteoporosis. Genetic studies investigating ALPL in humans and mice strongly implied the necessity of the gene in postnatal bone formation and that bone deformities were related to the degree of ALPL deficiency. Although the function of ALPL was established in bone development, its role in bone ageing remained unknown.

Bone ageing is the primary contributor to osteoporosis that also results in decreased bone mass and increased fat. Bone marrow mesenchymal stem cells are common progenitors of osteoblasts and adipocytes, undergoing senescence at the cellular level during bone ageing. Previous studies showed that rescuing the function of MSCs had significant therapeutic impact on ensuing regenerative capacity and bone mass. Yet, how ALPL orchestrated the differentiation and senescence of MSCs to affect bone ageing has remained elusive.

In the present study, the authors focused on the expression of ALP alongside tissue non-specific ALP (TNSALP) that is encoded as a cell surface marker to identify and isolate bone-forming stem cells. The combined expression and activity were detected using ALP activity assays, western blotting and immunohistochemistry in ageing mouse models. The scientists showed that bone ageing was associated with decreased Alpl expression in the bone marrow.

Gene knockout mice exhibited age-related bone mass loss and marrow fat gain compared to wild type mice, a) Serum ALP activities in 4-month old mice analyzed with ALP assays showed decreased activity in the knockout model [gene knockout (Alpl+/-) mice vs wild type (Alpl+/+)], b) Micro-CT images of bone marrow density decreased from 4-18 months in the Alpl+/- vs. Alpl+/+ mice, c-d) Oil red O staining images and quantification of the area of adipose tissue (red) from 4-18 months in the Alpl+/- vs. Alpl+/+ mice showed increased fat deposition in the mutant. Credit: Bone Research, doi: 10.1038/s41413-018-0029

The authors used gene knockout mouse models to investigate the regulatory role of Alpl in bone ageing (Alpl knockout: Alpl+/). Relative to the wild type group, the knockout mice showed nearly 50 percent reduction in serum ALP activity and mimicked premature bone ageing, accompanied with age-related bone mass loss and marrow fat gain. The study further showed that in MSCs, Alpl prevented bone ageing sensitivity by specifically regulating senescence and cell differentiation to govern the osteo-adipogenic balance of bone marrow stem cells.

Since the study showed that both Alpl and AMPKα pathway regulated the function of MSCs, metformin, a common activator of the AMPKα pathway, was introduced. Metformin is commonly known as a first-line drug used to treat type 2 diabetes, recently used as an anti-ageing drug while successfully extending the longevity and lifespan in experimental mice.

Metformin treatment prevented bone ageing in Alpl+/- mice. Metformin (60 mg/kg) was injected into the femoral bone marrow cavity of 4-month old mice, comparing the wild type (Alpl+/+) and mutants (Alpl+/-) with NaCl used as a control. Immunostaining analysis showed the expression of p-AMPKα (red) and nuclear staining (blue, DAPI). Quantification of the observation is indicated in the bottom panel. The AMPKα pathway was reactivated via metformin administration in the Alpl-deficient mice. Credit: Bone Research, doi: 10.1038/s41413-018-0029.

In the study, metformin demonstrated a stronger capacity to rescue the differentiation in knockdown MSCs in vitro and in knockdown mice in vivo, compared to the alternative therapeutic potential sought via the overexpression of the Alpl gene. Specifically, injections of metformin into the bone marrow cavity successfully rescued the impaired function of endogenous MSCs, while preventing premature bone ageing in the Alpl+/-mutant mice.

Collectively, the authors revealed a previously unrecognized role of Alpl gene in the prevention of bone ageing, with ATP-mediated functional alterations in MSCs and the potential of metformin treatment as an effective therapy in Alpl-deficient bone ageing. Future mechanistic studies at the cellular level will explore how Alpl regulates the ability of MSCs to release ATP and the broader impact of Alpl-deficiency on other organs.


Explore further:
Researchers discover gene that controls bone-to-fat ratio in bone marrow

More information:
Wenjia Liu et al. Alpl prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells, Bone Research (2018). DOI: 10.1038/s41413-018-0029-4

Vladimir N. Anisimov. Metformin: Do we finally have an anti-aging drug?, Cell Cycle (2013). DOI: 10.4161/cc.26928

Paolo Bianco et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine, Nature Medicine (2013). DOI: 10.1038/nm.3028

Journal reference:
Cell Cycle

Nature Medicine

Tagged with:

About author

Related Articles