Stanford University School of Medicine scientists have definitively linked mast cells, a class of cells belonging to the immune system, to the development of osteoarthritis, one of the world’s most common causes of pain and immobility.
In a study published online May 14 in eLife, the scientists demonstrated for the first time that banishing mast cells – or blocking signals from the most common stimulus activating them in real life, or disabling a cartilage-degrading enzyme they release when activated – all protected mice from developing osteoarthritis typically induced by a classic experimental procedure.
The results were supported by findings in human cells and tissues.
Osteoarthritis, by far the most frequently occurring variety of arthritis, is characterized by cartilage breakdown and inflammation in joints, which can be further aggravated by excess bone growths called osteophytes.
Some 30 million Americans have symptomatic osteoarthritis.
By time you’re 60, your chances of exhibiting osteoarthritis symptoms exceed 30 percent.
By age 80 or 90, your risk has risen to nearly 100 percent.
“Almost all of us will ultimately suffer from osteoarthritis if we live to be old enough,” said William Robinson, MD, Ph.D., professor of immunology and rheumatology, who is the study’s senior author.
Lead authorship is shared by research associate Qian Wang, MD, Ph.D.; former MD-Ph.D. student Christin Lepus, MD, Ph.D.; and former postdoctoral scholar Harini Raghu, Ph.D.
Not just wear and tear
Osteoarthritis has traditionally been thought to be an inevitable result of wear and tear: the breakdown of cartilage over many years, ultimately resulting in grinding, bone-on-bone contact and degeneration in the affected joints.
But the new study shows the essential involvement of the immune system in the genesis of osteoarthritis, while prying open a window through which researchers can see a way to designing drugs to prevent it.
At present, there are no drugs that can prevent, slow or cure it.
“Even though the vast majority of us will develop osteoarthritis at some point in our lives, we don’t have any disease-slowing therapies,” Robinson said.
The chances of actually reversing damage to joints are slim, he said.
Today’s treatments for the osteoarthritis-induced pain and mobility consist of painkillers like ibuprofen, naproxen and acetaminophen; walkers and canes; and knee or hip replacements.
Mast cells are best known as the culprits that produce the histamines and other molecules responsible for allergic symptoms, ranging from the itch of eczema to the mucous explosions of hay fever to the throat constriction of asthma or food-triggered anaphylaxis.
But mast cells also produce a degradative protein, tryptase, that can rip up collagens and other molecules that form the cartilage in joints.
Mast cells are important cells of the immune system and are of the hematopoietic lineage. Mast cells are originated from pluripotent progenitor cells of the bone marrow, and mature under the influence of the c-kit ligand and stem cell factor in the presence of other distinct growth factors provided by the microenvironment of the tissue where they are destined to reside. Under normal conditions, mature mast cells do not circulate in the bloodstream. However, mast cell progenitors migrate into tissues and differentiate into mast cells under the influence of stem cell factor and various cytokines. Mast cells are present throughout the body and they play important roles in the maintenance of many physiological functions as well as in the pathophysiology of diseases. Accordingly, this review is focused on the role of mast cells in a wide range of physiological functions and pathogenesis of a variety of disease states.
Human mast cells cultured from peripheral blood in SCF and stained with toluidine blue (cytoprep; 400×). The figure is provided courtesy of Madeleine K. Radinger (Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (LAD/NIAID/NIH). Images were obtained via digital microscopy using a Zeiss Axiophot (Jena, Germany) equipped with a Plan-Apochramat 100×/1.4 numeric aperature (NA) objective. Images were processed using Adobe Photoshop version 3.0 (Adobe Systems, San Jose, CA).
Location of Mast Cells
Mast cells are found in mucosal and epithelial tissues throughout the body. In rodents, mast cells also reside in peritoneal and thoracic cavities.
Mast cells are found in all vascularized tissues except for the central nervous system and the retina (1).
Mast cells are located at the junction point of the host and external environment at places of entry of antigen (gastrointestinal tract, skin, respiratory epithelium) (1–4).
Mast cells are located in areas below the epithelium in connective tissue surrounding blood cells, smooth muscle, mucous, and hair follicles.
The cytoplasm of the mast cell contains 50–200 large granules that store inflammatory mediators, including histamine, heparin, a variety of cytokines, chondroitin sulfate, and neutral proteases (1).
In order for mast cells to migrate to their target locations, the co-ordinated effects of integrins, adhesion molecules, chemokines, cytokines, and growth factors are necessary (5).
Mast cell progenitors are found in high numbers in the small intestine. CXCR2 expressed on mast cell progenitors directs their migration to the small intestine.
Binding of α4β7 integrins (expressed on mast cells) to adhesion molecule VCAM-1 on the endothelium initiates the transit of mast cell precursors out of the circulation (5).
The lungs do not have many mast cell progenitors in a normal physiological state. Upon antigen-induced inflammation of the respiratory endothelium, mast cell progenitors are recruited by engaging α4β7 integrins, VCAM-1, and CXCR2.
Additionally, CCR-2 and CCL-2 are involved in the recruitment of mast cell progenitors to the respiratory endothelium.
When mature mast cells are activated and degranulated, more mast cell progenitors are recruited to the site of inflammation (5).
There are two phenotypes of human mast cells: mucosal mast cells that produce only tryptase and connective tissue mast cells that produce chymase, tryptase, and carboxypeptidases (6, 7).
Mast cell activation and mediator release have different effects in various tissues and organs.
Most common sites in the body exposed to antigens are the mucosa of the respiratory tract (airborne), gastrointestinal tract (food borne), blood (wounds, absorption from respiratory tract/gastrointestinal tract), and connective tissues (8).
When the gastrointestinal tract is exposed to an antigen, its response is to increase fluid secretion, increase smooth muscle contraction, and increase peristalsis. Proteins derived from different plants and animals can act as antigens and activate the immune system in vulnerable subjects (8).
The antigen (peptide) permeates through the epithelial layer of the mucosa of the gut and binds to IgE on mucosal mast cells.
These peptides are presented to Th2 cells, and if there is an IgE antibody against the peptide present, it will cause activation of the mast cell resulting in an immune response.
This causes mast cells to degranulate and release a variety of inflammatory mediators.
These mediators increase vascular permeability, causing edema in the gut epithelium and smooth muscle contraction, which lead to vomiting and diarrhea.
This type of reaction can occur in response to peptides found in certain medications.
Food allergens can also cause skin reactions. Uptake from the gastrointestinal tract can introduce antigens into the blood, which are transported throughout the body where they bind to IgE on mast cells in the connective tissue in the deep layers of the skin. This results in urticarial reaction and angioedema (8).
In the respiratory tract, the immune response to mast cell activation results in airway constriction, increased mucous production, and cough (1).
The most common introduction of antigens to the respiratory tract is via inhalation. Mucosal mast cells in the nasal epithelium are activated by antigens that diffuse across the mucosa after being inhaled.
In the respiratory tract, mast cell degranulation increases vascular permeability and local edema, which can obstruct nasal airways and lead to congestion (9, 10).
There is increased production of mucus and its accumulation can block off the sinuses and result in a bacterial infection.
Mast cells also play a pivotal role in the pathophysiology of allergic asthma. This is caused by an inflammatory response in the airways, which results from inhaled antigens that get into the lower respiratory tract and cause mast cell degranulation and local inflammation.
These events lead to increased vascular permeability, fluid accumulation, and edema, which can obstruct the airways. Bronchial constriction can occur due to smooth muscle contraction, which can lead to airway obstruction that is seen in asthma.
Air is, therefore, trapped and total lung capacity is increased while forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) are decreased (8).
In the blood vessels, increased vascular permeability leads to edema and local inflammation, which results in antigen transport to the lymph nodes (11).
In the skin, antigens, via IgE, activate mast cells in the deep layers of connective tissue. Mast cells release histamine as well as other vasoactive molecules, which cause urticaria (hives). If the antigen activates mast cells in deeper tissue, this can lead to angioedema. If the response is prolonged, atopic dermatitis or eczema may occur. Eczema is seen clinically as a chronic itching skin rash with raised lesions and fluid discharge. Eczema is more commonly seen in childhood while allergic rhinitis and asthma are seen throughout life (8).
Mast cells usually reside quietly within tissues throughout the body. But when they become activated, they secrete granules containing histamines, tryptase and other inflammatory substances.
The classic trigger for that activation is the binding of a form of circulating antibody, or immunoglobin, called IgE to specialized receptors abounding on mast cells.
The evolutionary purpose of IgE, mast cells and histamines is believed to be to fight off parasites, which have plagued humans and other animals throughout most of evolution but have become relatively rare in humans in recent decades, at least in industrialized countries.
While mast cells have been found lurking in joints of people with and without symptomatic arthritis, until now neither mast cells nor IgE have been definitively identified as risk factors for osteoarthritis.
Protection from the disease
In the study, Robinson’s group used electron microscopy to show that mast cells in injured joints of humans who didn’t yet have arthritic symptoms weren’t releasing their histamine- and tryptase-laden granules, whereas mast cells residing in the joints of humans with arthritic symptoms were.
Several types of genetically altered lab mice whose mast cells were deficient or absent were highly resistant to the development of osteoarthritic features including joint inflammation, osteophyte development and joint breakdown after undergoing an experimental procedure to induce these symptoms, the researchers found.
The researchers also proved that impairing the action of tryptase, which is secreted almost solely by mast cells, had a similar protective effect.
And they further demonstrated that depleting IgE or its binding to receptors on mast cells, or disabling those receptors’ subsequent signaling to components within mast cells, all were protective.
In all, the scientists were able to get the same osteoarthritis-protective results using a number of genetic tricks, as well as three small-molecule compounds that each blocked a separate stage of the cascade via which IgE trips off mast-cell activation and secretion of granules containing collagen-chewing tryptase.
One drug used to impede mast cells’ survival, imatinib, is licensed by the Food and Drug Administration and marketed as Gleevec as a therapy for chronic myeloid lymphoma.
But while imatinib is an acceptable drug for such life-threatening cancers, Robinson said, it’s too toxic for sustained long-term use as a therapy in an indication such as osteoarthritis, which, although painful and mobility-reducing, is seldom directly life-threatening.
In any case, Robinson said, much of the joint damage caused by osteoarthritis is unlikely to be reversible.
“A major goal in my career is to find a way to stop people from getting osteoarthritis,” he said, adding that he wants to identify drugs with excellent safety profiles and the ability to prevent, rather than treat, osteoarthritis.
“These drugs will have to be safe enough for large numbers of people to take for decades without problems.”
More information: Qian Wang et al. IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis, eLife(2019). DOI: 10.7554/eLife.39905
Journal information: eLife
Provided by Stanford University Medical Center
