Breaking News
December 19, 2018 - Potential combination therapy against rare disease of the bone marrow could improve treatment
December 19, 2018 - UC San Diego Health offers new DRG stimulation device for phantom limb pain
December 19, 2018 - Study examines relationship between growth restriction and risk of childhood mortality
December 19, 2018 - New study provides insights on increased risk of suicide in young patients visiting ED
December 19, 2018 - AHA: Thyroid Problems Linked to Worsening Heart Failure
December 19, 2018 - World-first coeliac disease vaccine enters Phase 2 trials
December 19, 2018 - RNA sequencing offers novel insights into the microbiome
December 19, 2018 - A promising, effective vaccine for common respiratory disease
December 19, 2018 - Protein may slow progression of emphysema, study finds
December 19, 2018 - Studying atrial fibrillation — and exploring new frontiers in precision health
December 19, 2018 - A New Way To Get College Students Through A Psychiatric Crisis — And Back To School
December 19, 2018 - Optum, UnitedHealthcare take action to help people affected by North Carolina winter storms
December 18, 2018 - Weight change in middle-aged, elderly Chinese Singaporeans related to increased risk of death
December 18, 2018 - Immune cells sacrifice themselves to protect us from invading bacteria
December 18, 2018 - Watching brain cells fire, with a twist of gravitational waves
December 18, 2018 - 2018 in Review
December 18, 2018 - Getting the Most Out of the CLARITY Technique
December 18, 2018 - NVF shoes provide a viable option for track and road racing
December 18, 2018 - CRISPR may restore effectiveness of chemotherapies used to treat lung cancer
December 18, 2018 - New app accurately measures and charts progression of skin wounds
December 18, 2018 - Persistent Discrimination ID’d Among Physician Mothers
December 18, 2018 - Cellphone technology developed to detect HIV
December 18, 2018 - A Stanford doctor hits the field with the 49ers — as their airway management physician
December 18, 2018 - The Rise of Anxiety Baking
December 18, 2018 - Just one night of sleep deprivation increases the urge to eat
December 18, 2018 - Study reveals mechanism behind failed remyelination in MS
December 18, 2018 - New genetic testing method increases the precision of biomarker analysis
December 18, 2018 - Simple technique to effectively treat underdiagnosed cause of debilitating chest pain
December 18, 2018 - Barbershop-based medical intervention can successfully lower blood pressure, new data shows
December 18, 2018 - Food labels have caused changes in consumers’ intake and industry’s use of key additives
December 18, 2018 - Sickest children could benefit from split liver transplants
December 18, 2018 - Scientists create patient-specific model to identify most effective treatment for appendix cancer
December 18, 2018 - ‘Little Foot’ endocast reveals a small brain combining ape-like and human-like features
December 18, 2018 - New therapy for childhood blindness shows ‘very promising’ results
December 18, 2018 - Researchers discover promising new compound against Buruli ulcer
December 18, 2018 - Study finds significant use of traditional, complementary and alternative medicines in Sub-Saharan Africa
December 18, 2018 - California Farm Implicated in Outbreak of E. coli Tied to Romaine Lettuce
December 18, 2018 - Mobile health has power to transform HIV/AIDS nursing
December 18, 2018 - Celiac Vaccine in Clinical Trials at Columbia
December 18, 2018 - Research into mental health first aid prompts practical guidance and resources for workplace
December 18, 2018 - Researcher conducts study to investigate peripheral blood markers of Alzheimer’s disease
December 18, 2018 - Researchers identify link between mucus in the small airways and pulmonary fibrosis
December 18, 2018 - EU Commission’s Health Policy Platform to host EKHA program on transplantation
December 18, 2018 - Survivors of childhood Hodgkin lymphoma have high risk of developing solid tumors
December 18, 2018 - Small changes to cafeteria design can get kids to eat healthier, new assessment tool finds
December 18, 2018 - From Machines to Cyclic Compounds
December 18, 2018 - New study reveals best assessment tools to establish delirium severity
December 18, 2018 - Rice University scientists develop synthetic protein switches to control electron flow
December 18, 2018 - Home-based pulmonary function monitoring for teens with Duchenne muscular dystrophy
December 18, 2018 - Researchers identify potential target for new breast cancer treatments
December 18, 2018 - National Biofilms Innovation Centre award grant to Neem Biotech for novel anti-biofilm drug development
December 18, 2018 - Artificial intelligence and the future of medicine
December 18, 2018 - Montana State doctoral student receives grant for her work to improve neuroscience tool
December 18, 2018 - Early postpartum initiation of opioids associated with persistent use
December 18, 2018 - Russian scientists identify molecular ‘switch’ that could be target for treatment of allergic asthma
December 18, 2018 - Surgeons make more mistakes in the operating room during stressful moments, shows study
December 18, 2018 - Immune cells explode themselves to inform about the danger of invading bacteria
December 18, 2018 - Malnutrition in children with Crohn’s disease linked with increased risk of surgical complications
December 18, 2018 - FDA Approves Motegrity (prucalopride) for Adults with Chronic Idiopathic Constipation (CIC)
December 18, 2018 - The long and short of CDK12
December 18, 2018 - Hologic’s Cynosure division introduces TempSure Surgical RF technology in North America
December 18, 2018 - CMR Surgical partners with Nicholson Center to launch U.S.-based training program for Versius
December 18, 2018 - Findings reinforce guidelines for cautious use of antipsychotics in younger populations
December 18, 2018 - Study finds new strains of hepatitis C virus in sub-Saharan Africa
December 18, 2018 - New battery-free, implantable device aids weight loss
December 18, 2018 - Parental alcohol use disorder associated with offspring marital outcomes
December 18, 2018 - Novel Breast Imaging Technique Might Cut Unnecessary Biopsies
December 18, 2018 - What can a snowflake teach us about how cancer spreads in the body?
December 18, 2018 - Management of nausea and vomiting in pregnancy costs the NHS more than previously thought
December 18, 2018 - Green leafy vegetables may reduce risk of developing liver steatosis
December 18, 2018 - Veganism linked to nutrient deficiencies and malnutrition if not planned correctly
December 18, 2018 - Coming Soon: A Tiny Robot You Swallow to Help You Stay Healthy
December 18, 2018 - Modified malaria drug proven effective at inhibiting Ebola
December 18, 2018 - Study finds epigenetic differences in the brains of individuals with schizophrenia
December 18, 2018 - Fitness instructors’ motivational comments influence women’s body satisfaction
December 18, 2018 - Study focuses on modification of lipid nanoparticles for successful brain cell targeting
December 18, 2018 - New gut bacteria may be effective against obesity, metabolic and mental disorders
December 18, 2018 - New two-in-one powder aerosol to upgrade fight against deadly superbugs in lungs
December 18, 2018 - Biofilms feed with swirling flows
December 17, 2018 - Study identifies specific neurological changes related to traumatic brain injury
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