Connective Tissue

Connective tissue consists of cells, ground substance (a clear, colorless, viscous fluid or sometimes hardened filling the space between the cells and fibers), and three protein fibers to make up the extracellular matrix. Collagen fibers contain glycoproteins and are the most prominent to provide the tendons and ligaments with strength. Elastic fibers consist of elastin protein and some glycoprotein, and other proteins with the ability to stretch and return to their original shape. Elastic fibers are in the skin, lungs, arteries, veins, elastic cartilage, periodontal ligament, and vertebral column. Made of similar proteins as collagen fibers but long and branching, reticular fibers are throughout the body, particularly in the reticular tissue of the liver, spleen, and lymphatic tissue. ³

All tissues consist of cells, but connective tissue cells are packed loosely within the extracellular matrix.⁴ Connective tissue comprises two broad categories based on the cells and the extracellular matrix–connective tissue proper and specialized connective tissue.

Connective Tissue Proper includes:

1. Loose connective tissue (subcategorized into areolar, adipose, and reticular) contains collagenous, reticular, and elastic fibers with a ground substance. The most widely distributed, the loose connective tissue, joins the cells in other tissues such as muscles, epithelia, and nerves.⁵ This tissue can be found in most organs and supports immunity, mechanical and metabolic activity.
2. Dense connective tissue (dense regular, elastic, dense-irregular) is highly compressed collagenous fibers to make up the walls of large arteries, dermal layer of skin, tendons, and ligaments.

Specialized Connective Tissue includes:

1. Bone -Like all connective tissue, bone consists of a mineralized extracellular matrix and ground substance. Bone provides weight-bearing and protective functions. It also stores calcium and phosphate. ⁴
2. Cartilage - (hyaline, fibrocartilage, and elastic). The most common cartilage is hyaline cartilage found in the nose, ribs, trachea, and larynx. Fibrocartilage is the strongest cartilage located in invertebral discs, joint capsules, and ligaments. Elastic cartilage helps maintain shape while providing strength and elasticity in the external ear, epiglottis, and larynx.⁶
3. Blood and Lymph - The blood and lymph systems consist of a liquid extracellular matrix. The blood is responsible for transporting oxygen, carbon dioxide, nutrients, wastes, and salts, defending against harmful microorganisms and blood clotting. The lymph system drains and delivers molecules into the blood, including fat absorbed by the intestine, and carries excess interstitial fluid.⁷
4. Adipose Tissue – Composed of adipocytes or lipid cells, adipose tissue is categorized as white or brown tissue. White adipose tissue is plentiful in the body beneath the skin, around organs, and in the bone marrow. Its purpose is to store energy, insulate, and cushion the body. Brown adipose tissue is found in the fetus and infants along the upper back and helps prevent hypothermia in infants.⁸
5. Reticular Connective Tissue - is made up of reticular fibers (type III collagen) to form a mesh-like, supportive framework for soft organs such as lymphatic tissue, the spleen, and the liver.⁹ This connective tissue is also found in the bone marrow.
6. Embryonic Connective Tissue – is formed in the embryo's development and consists of mesenchyme which matures into the various connective tissues of the body, and mucoid connective tissue, which is a gelatinous substance found in the umbilical cord.¹⁰

Connective tissue contributes to restoring fuel and transporting substances in the body. Different types of connective tissue have varying vascularity. Bone, for instance, is highly vascular, while tendons, ligaments, and cartilage have little to no blood supply.¹¹ Due to the lack of blood supply, cartilaginous tissue is slow to heal.

Connective tissue diseases are autoimmune disorders (characterized by autoantibodies) that affect the collagen and elastin proteins. Over two hundred connective tissue disorders can be classified as genetic disorders (Heritable Disorders of Connective Tissue (HDCTs), autoimmune disorders, or cancer. ¹² Examples of heritable disorders of connective Tissue are Ehlers-Danlos syndrome (EDS), Epidermolysis bullosa (EB), Marfan syndrome, and Osteogenesis imperfecta. Some common autoimmune connective tissue disorders include Rheumatoid arthritis (which can also be inherited), Scleroderma, Mixed connective tissue disease, Undifferentiated connective tissue disease, Systemic lupus erythematosus, Sjögren's syndrome, and Psoriatic arthritis. Soft tissue sarcoma is a connective tissue cancer that can occur anywhere in the body. ¹³

Based on the patient's symptoms, family history, and physical exam findings, a physician may order the following:

• Complete blood count
• Inflammatory markers (Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
• Antinuclear antibodies (ANA). The American College of Rheumatology supports the immunofluorescence antinuclear antibody test using Human Epithelial type 2 (HEp-2) substrate as the gold standard for ANA testing. ¹⁴
• Rheumatoid factor
• Imaging tests (X-rays or MRI)
• Urine tests
• Tissue biopsy – performed to determine the diagnosis, organ involvement, and therapy efficacy. ¹⁵
• Other first-line tests for differential diagnosis include dsDNA, IgG; Smith/RNP, IgG; Smith (ENA), IgG; SSA 52 and 60, IgG; SSB, IgG; Jo-1, IgG; Scl-70, IgG. ¹⁶ (The Choosing Wisely Campaign recommends not ordering ANA subserologies if the ANA is not positive.) ¹⁷

Connective tissue is the most abundant tissue in the body that serves to attach, support, protect, insulate, store reserve fuel, and transport substances within the body. ¹⁸ Connective tissue disorders are varied and can affect many body areas. Treatment is different with each disease. There is ongoing research on biomarkers to aid in the diagnosis, early detection, prediction of disease progression, and treatment.¹⁹ For those with a connective tissue disorder, support and advocacy groups can direct patients and families to resources and services. ²⁰

To learn more about the staining process in the laboratory after a tissue biopsy, visit Special Stains – Which One, How, and Why? Part II: Connective Tissue