Connective Tissue

Connective tissues create the form of the human body, the proper tissues for strength and flexibility, as well as, the distinct pathways for nutrients to reach the multitude of cells throughout the body. Connective tissues transmit the small individual forces that become the massive precise symphony that allow us to move within our environment.  They also reduce the friction between adjacent structures and protect the delicate nerves and blood vessels from injury. The health of the connective tissue determines the extent of tissue repair following injuries as it is responsible for reestablishing the underlying matrix that is home to the specialized cellular components of each tissue. The biological health and activity of the connective tissue is dependent on the level of hydration, the cellular composition as well as the presence of specific proteinases, growth factors, and cytokines (September, 2007). The primary fuel source for tissue maintenance and wound repair is glucose that is found in the tissues, not the glucose that is common in the blood vessels (Broughton, 2006). The individual components of connective tissues include a variety of different types of collagen tissues, the space between collagen fibers called the extracellular matrix (ECM), and the specialized cells that are responsible for the maintenance of the connective tissue.

Collagen

Connective tissues include the bone, cartilage, fascia, tendons, and ligaments. Collagen is the major component of all connective tissues. Collagen provides tissues with tensile strength and stiffness. There are twenty-eight different types of collagen that have been identified to date (Pawelec, 2016). Collagen makes up 30% of the total protein mass of the extracellular matrix (Franz, 2010).  Collagen is produced by fibroblasts which organize the fibers into fibrils then into larger cords and sheets that align in the direction of force within the individual tissues (Franz, 2010). Collagen fibers can withstand tension and compression and remain stiff and inelastic. Collagen only becomes flexible and elastic when the fibers are woven or bundled together; this allows them to recoil with the release of tension. Crimp describes this phenomenon where the woven bundles are aligned in a sinusoidal pattern that is parallel to mechanical stress allowing for shock absorption and the elongation of the collagen without damage (Amiel, 1982). The most common mature collagen is known as type I, and it is abundant in tissues that are subject to high tensile forces such as tendons. Type II collagen is found in structures that endure compressive forces such as cartilage. Type III collagen is the immature and weaker form that is created early in the healing process and eventually transitions into more mature collagen types. At the molecular level, collagen is synthesized as procollagen molecules by fibroblasts and then secreted into the extracellular space (Frank, 2004).The helical collagen molecules line up to form microfibrils which make up fibrils then subsequently collagen fibers that make up connective tissues. Lysyl oxidase promotes the placement of crosslinks within and between the collagen molecules. The greater the crosslinking of collagen, the stronger the structure (Frank, 2004).

Elastin

Elastin is found mostly in the skin and some connective tissues. Elastin allows tissues to recoil from repeated stretch (Franz, 2010). The ligamentum flavum in the spine is made up of a 2:1 distribution of elastin and collagen (Nachemson, 1968) giving it the ability to recoil with repeated spinal flexion and extension. Unfortunately, over time capacity to recoil decreases resulting in a common condition called spinal stenosis.

Extracellular matrix

The extracellular matrix describes the non-cellular component of tissues and is comprised of loose collagen fibers and amorphous ground substance. The extracellular matrix makes up 80% of the total body tissue volume, of which two-thirds is water.  The ECM provides the intimate cellular scaffolding and initiates the cues for tissue adaptation (Franz, 2010). It also plays a major role in force transmission and the continuous maintenance of the tissue structures (Kjaer, 2004).

Amorphous ground substance

Amorphous ground substance or proteoglycans (protein-carbohydrate structures) attract water and form a gel which facilitates the diffusion of materials between cells. It results in the particular tissue characteristic of individual tissues (Franz, 2010). Greater hydration results in a semisolid structure which resists compressive forces such as those that occur in joint cartilage. Ligamentous tissues handle more multi-directional tensile forces than compressive forces, so they have less water content than cartilage but greater water content than tendons (Amiel, 1982). Tendons can resist the greatest unidirectional tensile forces. Hence they have the most tightly packed collagen fibers leaving little room for proteoglycans and water (Amiel, 1982).

Specialized Cells

Specialized cells such as the fibroblasts, macrophages and mast cells comprise 20% of the total volume of connective tissue (September, 2007). Fibroblasts produce the collagen fibers and the amorphous ground substance that are vital in tissue repair. Fibroblasts are related to other cells that create tissues such as osteoblasts (bone formation cells) and chondroblasts (cartilage formation cells). A subset of fibroblasts called, myofibroblasts use contractile elements within the cell to assist in wound closure. Corticosteroids inhibit fibroblast activity resulting in incomplete or delayed wound healing.

Macrophages

Macrophages exist as circulating monocytes in the vascular system and are responsible for phagocytosis and scar formation. They act to debride the wound in preparation for healing and activate fibroblast activity. Macrophages increase local satellite cell differentiation for repair and increase muscle fiber proliferation (Grefte, 2007). Hence muscle regeneration is reduced with fewer macrophages (Shen, 2008). Corticosteroids have also been found to inhibit macrophage activity delaying fiber production (Fowler, 1989).

Mast cells

Mast cells contain secretory organelles which utilize arachidonic acid to produce inflammatory proteins called leukotrienes. They also contain cytokines, histamine, heparin, and serotonin. Chemical or mechanical stimuli can cause the release of these chemicals. Histamine causes vasodilatation and heparin causes anticoagulation which allows fluid and blood components to collect in the injured area to begin the healing cascade. Serotonin results in vasoconstriction which creates the typical painful response following tissue injury (Theoharides, 2012). The healing cascade continues until the wound completely heals and the connective tissues mature.

References

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  2. Amiel D, Woo SL, Harwood FL, Akeson WH. The effect of immobilization on collagen turnover in connective tissue: a biochemical-biomechanical correlation.  Acta Orthop Scand. 1982 Jun;53(3):325-32.

  3. Amiel, D., Akeson, W.H., Harwood, F.L., 1983. Stress deprivation effect on metabolic turnover of the medial collateral ligament collagen: a comparison between 9- and 12-week immobilization. Clinical Orthopaedics and Related Research 172, 265–270.

  4. Broughton G 2nd, Janis JE, Attinger CE. Wound healing: an overview. Plast Reconstr Surg. 2006 Jun;117(7 Suppl):1e-S-32e-S.

  5. Fowler JD. Wound healing: an overview. Semin Vet Med Surg (Small Anim). 1989 Nov;4(4):256-62.

  6. Frank CB. Ligament structure, physiology and function. J Musculoskel Neuron Interact 2004; 4(2): 199-201.

  7. Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010 Dec 15;123(Pt 24):4195-200.

  8. Grefte S, Kuijpers-Jagtman AM, Torensma R, Von den Hoff JW. Skeletal muscle development and regeneration. Stem Cells Dev. 2007 Oct;16(5):857-68.

  9. Kjaer M. Role of extracellular matrix in adaptation of tendon and skeletal Muscle to mechanical loading. Physiol Rev. 2004 Apr;84(2):649-98.

  10. Perkins, G. Rest and movement. J Bone Joint Surg Br. 1953 Nov;35-B(4):521-39.

  11. Nachemson AL, Evans JH. Some mechanical properties of the third human lumbar interlaminar ligament (ligamentum flavum). J Biomech. 1968 Aug;1(3):211-20.

  12. September AV, Schwellnus MP, Collins M. Tendon and ligament injuries: the genetic component. Br J Sports Med. 2007 Apr;41(4):241-6.

  13. Shen W, Li Y, Zhu J, Schwendener R, Huard J. Interaction between macrophages, TGF-beta1, and the COX-2 pathway during the inflammatory phase of skeletal muscle healing after injury. J Cell Physiol. 2008 Feb;214(2):405-12.

  14. Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, Kalogeromitros D. Mast cells and inflammation. Biochim Biophys Acta. 2012 Jan;1822(1):21-33.

Andre Panagos, MD

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