Breaking News
March 22, 2019 - TMJ disorders could be treated with tissue-engineered implants after successful animal study
March 22, 2019 - Team-based approach is key to successful care of pregnant women with heart failure
March 22, 2019 - Study identifies gene variant associated with accelerated cellular aging
March 21, 2019 - Salk scientists show how background noise from neurons can interrupt focused attention
March 21, 2019 - New class of drugs could help treat patients diagnosed with ovarian cancer
March 21, 2019 - Tecentriq Approved for Small Cell Lung Cancer
March 21, 2019 - Adipocyte glucocorticoid receptors play a role in developing steroid diabetes
March 21, 2019 - Climate change can affect nutrient content of crops, harming human health
March 21, 2019 - Podcast: KHN’s ‘What The Health’ Surprise! Fixing Surprise Medical Bills Is Harder Than it Looks
March 21, 2019 - Chemistry researchers patent new method for making anti-leukemia compounds
March 21, 2019 - UIC scientists identify hidden proteins in bacteria
March 21, 2019 - New Australian drug trial achieves remarkable results in patients with acute myeloid leukemia
March 21, 2019 - Females live longer when they have help raising offspring
March 21, 2019 - How did orthodontists sell orthodontics?
March 21, 2019 - In the Spotlight: From dietitian to physician assistant student
March 21, 2019 - The CRISPR Revolution: What You Need to Know
March 21, 2019 - FDA Chief Calls For Stricter Scrutiny Of Electronic Health Records
March 21, 2019 - Combined glucocorticoid and antioxidant therapy could benefit premature babies
March 21, 2019 - Low levels of certain eye proteins could serve as predictor for Alzheimer’s
March 21, 2019 - Post-traumatic holocaust survivors transmit negative views on aging to offspring
March 21, 2019 - City of Hope receives $7.5 million in grant awards to study cutaneous T cell lymphoma
March 21, 2019 - New video game-led training device helps stroke survivors regain arm mobility
March 21, 2019 - Compounds in coffee could slow prostate cancer growth
March 21, 2019 - New mobile DNA element in Wolbachia may contribute to improved disease control strategies
March 21, 2019 - Phase 2 Clinical Trial of Bermekimab Shows Potential New Standard of Care for Treatment of Hidradenitis Suppurativa, Including Significant Pain Reduction without Antibiotics
March 21, 2019 - More than one-third of patients risk major bleeding by doubling up on blood thinners
March 21, 2019 - A skeptical look at popular diets: Thumbs up for Mediterranean
March 21, 2019 - PTSD After Cardiac Arrest Predicts More Heart Trouble
March 21, 2019 - Role of immunological imprinting in elicitation of new antibodies
March 21, 2019 - Breast cancer relapse predictor tool may soon be a reality
March 21, 2019 - New computer program developed by TGen lights up cancer-causing genetic mutations
March 21, 2019 - FDA warns two breast implant makers for failure to comply with post-approval study requirements
March 21, 2019 - Butler Hospital receives COBRE grant to enhance research on neuropsychiatric illnesses
March 21, 2019 - Majority of osteoporosis clinical practice guidelines ignore patients’ voices
March 21, 2019 - Generic messages don’t help patients to lose weight
March 21, 2019 - Eisai and Imbrium Therapeutics Announce U.S. FDA Filing Acceptance of New Drug Application for Lemborexant for the Treatment of Insomnia
March 21, 2019 - Two-drug combos using popular calcium channel blocker show superiority in lowering BP
March 21, 2019 - Itamar Medical launches next-generation WatchPAT system for home sleep apnea testing
March 21, 2019 - Study estimates health and economic impacts of healthy food prescriptions
March 21, 2019 - Detecting fungal disease in crops with multispectral imaging system
March 21, 2019 - MIT announces creation of the Alana Down Syndrome Center
March 21, 2019 - Next-generation LVAD device clinically superior, safer for heart failure patients
March 21, 2019 - Allergan Announces FDA Approval of Avycaz (ceftazidime and avibactam) for Pediatric Patients
March 21, 2019 - Mutations in noncoding genes could play big role in regulating cancer, study finds
March 21, 2019 - A medical student’s thoughts on Match Day
March 21, 2019 - Are eggs good or bad for you?
March 21, 2019 - New analysis reveals precision oncology insights for colorectal cancer
March 21, 2019 - Pollutants appear to weaken immune system and increase pathogen virulence
March 21, 2019 - Researchers develop and validate scale for rating severity of mononucleosis
March 21, 2019 - Scientists identify generation of key immune response in mice on introducing solid food
March 21, 2019 - New nanomaterial could restore internal structure of damaged bones
March 21, 2019 - Selective destruction of prostate tumor as effective as complete prostate removal
March 21, 2019 - 2011 to 2015 Saw Increase in Psychiatric ED Visits for Youth
March 21, 2019 - Tapeworm drug targets common vulnerability in tumor cells
March 21, 2019 - WVU researcher discovers higher suicide rate among Medicaid-insured youth
March 21, 2019 - Off the beaten path for global health residency
March 21, 2019 - European Parliament’s report calls on EU to develop policies to regulate endocrine-disrupting chemicals
March 21, 2019 - Women with undiagnosed diabetes in pregnancy more likely to experience stillbirths
March 21, 2019 - Fish consumption can help prevent asthma, study reveals
March 21, 2019 - Royal Holloway professors to lead new to research into curing Neurofibromatosis type 1
March 21, 2019 - NSF offers grant to improve treatment approaches for pelvic organ prolapse
March 21, 2019 - Your Apple Watch Might Help Spot a Dangerous Irregular Heartbeat
March 21, 2019 - Research team uncovers critical new clues about what goes awry in autistic brains
March 21, 2019 - From March Madness to medicine with help from mentors
March 21, 2019 - Mental health disorders among young adults may be on the increase
March 21, 2019 - New study examines smarter automatic defibrillator
March 21, 2019 - UC Riverside research shows how natural selection favors cheaters
March 21, 2019 - Mother’s diet during pregnancy can impact lung-specific genes of her offspring
March 21, 2019 - AeroForm Tissue Expanders makes breast reconstruction after mastectomy more comfortable
March 21, 2019 - New project focuses on creating more responsive, intuitive prosthetics
March 21, 2019 - New case study describes adolescent patient with rapid-onset schizophrenia and Bartonella infection
March 21, 2019 - Umass Amherst food scientist honored with 2019 Young Scientist Research Award
March 21, 2019 - Smell of skin could lead to early diagnosis for Parkinson’s
March 21, 2019 - Difference in brain connectivity may explain autism spectrum disorder
March 21, 2019 - Untangling the microbiome — with statistics
March 21, 2019 - Human microbiome metabolites enhance colon injury by enterohemorrhagic E. coli, study shows
March 21, 2019 - Written media can improve citizens’ understanding of palliative care
March 21, 2019 - New research aims to find how asthma symptoms are aggravated
March 21, 2019 - New $9.7 million NIH grant project seeks to improve hearing restoration
March 21, 2019 - Researchers measure brain metabolite levels in people with mild memory problems
Defense against joint degeneration

Defense against joint degeneration

image_pdfDownload PDFimage_print
The role of ITGBL1 in facial cartilage development in X. laevis embryos. A) Alcian blue-stained images of craniofacial cartilages in control and Itgbl1-rescued embryos of X. laevis. Upper panels show ethmoidal plates and lower panels show the ceratohyal cartilages. B) Alcian blue-stained images of craniofacial cartilages of control and Itgbl1-overexpressing embryos. Credit: Science Translational Medicine, doi: 10.1126/scitranslmed.aam7486.

During cartilage development, chondrocytes secrete the extracellular matrix (ECM) and embed within the same environment. During progressive joint disease, such as osteoarthritis (OA), dysregulation of the process can lead to ECM degradation. In a recent study, Eun Kyung Song and co-workers examined samples of cartilage from patients with OA and found reduced expression of integrin-β-like 1 (ITGBL1) (an integrin inhibitory protein expressed during cartilage development) secreted in the samples. Depletion of the ITGBL1 protein reduced ECM deposition, leading to cartilage damage. Conversely, overexpression of the protein prevented knee joint degeneration in a mouse model of surgically induced OA. The study identified a target to modulate integrin signaling, with potential for therapeutic effects in OA. The results are now published in Science Translational Medicine.

Chondrocytes constantly interact with and remodel the surrounding ECM during development and maturation. During cartilage formation (chondrogenesis), the integrin-ECM is regulated differently. Integrin signaling is key to catabolic responses that lead to joint destruction in rheumatoid arthritis and osteoarthritis. The inherent ability of chondrocytes to regulate integrin-signaling in an ECM-rich environment remains poorly understood. In the study, the researchers found that developing chondrocytes expressed the Itgbl1 (integrin-β-like 1) gene, at specific stages to inhibit integrin signaling and promote chondrogenesis. Unlike inhibitors of integrin in the cytosol, ITGBL1 is physically secreted to interact with integrins and down-regulate their activity. In patients with osteoarthritis, Itgbl1 expression was strongly reduced in the damaged articular cartilage. Comparatively, the expression of ectopic Itgbl1 protected joint cartilage against OA development in the destabilization of the medial-meniscus (DMM) induced OA mouse model. The results revealed that ITGBL1 signaling was an underlying mechanism protecting against destructive cartilage disorders. Targeting ITGBL1 can yield potential therapeutic results by modulating integrin signaling in human disease.

The ECM-driven signaling process is essential for the pathophysiology of destructive cartilage disorders. The interaction between ECM-chondrocyte is mainly mediated by integrins; heterodimeric receptors for ECM molecules including fibronectin, collagen and laminin. Various subunits of integrin-α and integrin-β are expressed by chondrocytes. The profile of integrin expression is dynamically regulated during chondrogenic differentiation and development of osteoarthritis. Currently there is limited understanding on how developing and mature chondrocytes dynamically regulate integrin signaling, alongside the potential of integrins to exert negative effects on cartilage formation.

The ITGBL1 protein was originally termed “ten beta integrin EGF” (epidermal-growth factor)-like repeat domains” due to its secondary structure. Recent studies have indicated the role of the protein during cancer cell migration and in liver fibrosis. The molecular function of ITGBL1 has remained unexamined in developing animals. In vertebrates, including Xenopus laevis (frog), mouse and human, the function of ITGBL1 is highly conserved. In damaged articular chondrocytes from patients with OA, the genetic expression of ltgb1 decreased. The authors used a mouse model of surgically induced OA, to show the protective role of ITGBL1 against OA development in joint cartilage in the study.

Functions of ITGBL1 during chondrogenesis in mouse and human cells. A) Frozen sections of control and ITGBL1-depleted hBMSC-derived chondrogenic-pellets stained with an anti-COL2A1 antibody or B) Alcian blue. C) Mouse limb-bud mesenchyme isolated and induced for chondrogenesis by serum (S+) or by overexpressing Itgbl1 without serum (S-), stained with Alcian blue. Credit: Science Translational Medicine, doi: 10.1126/scitranslmed.aam7486.

The authors further explored the mechanism of action of the protein in chondrogenic differentiation within human bone marrow-derived mesenchymal stem cells (hBMSCs). In the experiments, the authors conducted RT-PCR to reveal that the Itgbl1 gene expression gradually increased during differentiation within chondrogenic hBMSCs. When small interfering RNA mediated Itgbl1 knockdown was conducted in hBMSCs, with subsequent induction of chondrogenesis, the Itgbl1 gene expression effectively decreased. The results were observed with immunostaining where control hBMSCs deposited chondrogenic ECM normally, whereas the Itgbl1 knockdown reduced chondrogenic ECM and collagen expression.

The study thereafter confirmed the protective role of ITGBL1 against the development of OA in a mouse model in vivo. Depletion of ITGBL1 induced OA-like damage in joint cartilages, which was partially recovered by the inhibition of integrin-α5β1 activities. The results were consistent with a previous study where chondrocyte-specific deletion of integrin alpha 5 protected against OA development. The authors administered an integrin alpha 5 inhibitor, ATN-161 to the animal model displaying OA damage. Although a full recovery to OA-like damage wasn’t observed, the lack of recovery was attributed to the activation of other types of integrins that weren’t inhibited by ATN-161.

ITGBL1 expression protects cartilages from OA development. A) Alcian blue staining and ITGBL1 protein expression (immunohistochemistry – IHC) (upper panel) and mRNA (lower plot) in cartilage samples from human patients with OA and undamaged controls. B) Safranin-O staining and immunohistochemistry of destabilization of the medial meniscus (DMM) mouse model of OA; knees injected with Ad-Itgbl1 or control. Credit: Science Translational Medicine, doi: 10.1126/scitranslmed.aam7486

Beyond targeting chondrocytes, the fragmented ECM molecules also triggered inflammation responses in other cells. These included synovial fibroblasts, macrophages and immune cells expressed during inflammatory conditions such as rheumatoid arthritis. In the development of arthritis many integrin subunits are dynamically expressed in various cell types. As a result of the sub-type specific nature of integrin inhibitors, it is very challenging to reduce integrin-mediated destructive signals from all cell types.

At present, while an increasing number of patients suffer from OA, most treatments only relieve the symptoms without approved medicines to effectively restore damaged cartilage. The study found that the level of Itgbl1 expression in human chondrocytes from patients with OA decreased. The in vivo studies in animal models showed that ITGBL1 functioned in cartilage development, actively maintained cartilage and protected it from destructive signals. Unlike several other biological forms of integrin inhibitors, ITGBL1 was secreted to reduce integrin signaling by physically interacting with integrin. The unique function of the protein ITGBL1, with its role as a secreted inhibitor of integrin points to new approaches of treating destructive cartilage disorders and integrin-mediated human diseases.


Explore further:
Scientists found means to inhibit capillary leakage in sepsis

More information:
Eun Kyung Song et al. ITGBL1 modulates integrin activity to promote cartilage formation and protect against arthritis, Science Translational Medicine (2018). DOI: 10.1126/scitranslmed.aam7486

Journal reference:
Science Translational Medicine

Tagged with:

About author

Related Articles