This time, let us focus on collagen, which is deeply connected to bone health. In previous articles, we examined how bones are formed when calcium and phosphorus are deposited onto organic matter—about 90% of which is composed of collagen (Type I Collagen). When discussing new bone formation, people often think of calcium or minerals first, but collagen plays just as significant a role in bone formation as these mineral components. Let's take a closer look at collagen.
Collagen is, without exaggeration, the most abundant protein in the human body. It is found in almost all connective tissues, including skin, eyes, blood vessels, bones, joints, tendons, and ligaments, and is a key component of the extracellular matrix. In other words, it is a structural protein that exists throughout the human body. Like rebar in a building, collagen provides strong structural support to tissues while offering elasticity and stability. In the skin, it helps maintain elasticity and firmness; in bones, it provides not only strength but also the flexibility needed to prevent fractures; in cartilage and ligaments, it absorbs shock and enables smooth joint movement. Collagen is a high molecular weight protein that supports and maintains cellular structures throughout the body.
Types of Collagen
To date, 28 different types of collagen have been identified, with types I, II, III, and IV being the most well-known. Type I collagen, in particular, is the most representative form, making up over 90% of the body’s total collagen. Collagen can be broadly classified into fibrillar (classical) and non-fibrillar (non-classical) types. Fibrillar collagen is composed of three polypeptide chains that form a triple helix, which then self-align and assemble into long, continuous fibrils. These provide mechanical strength and include types I, II, III, V, and XI.
Non-fibrillar collagens, on the other hand, form mesh-like or anchoring structures that interact with other fibers to support tissue connectivity and stability. This group includes types IV, VI, VII, XII, and XIV. Classical and non-classical collagens interact with one another and can form various composite structures depending on the type and function of the tissue. The following diagram illustrates how basic collagen units combine to form diverse structures to perform different functions.
Collagen Biosynthesis
Fibroblasts
Before delving into the biosynthesis of collagen, let us briefly take a look at fibroblasts, the main cells responsible for producing collagen. Fibroblasts are the primary cells that make up loose connective tissue. A characteristic feature of connective tissues is that their extracellular matrix (ECM) and interstitial components far exceed the proportion of cells. Fibroblasts secrete key ECM components and the enzymes necessary for ECM remodeling. These include fibrous proteins like collagen, elastin, and reticular fibers, as well as non-fibrous ECM components like glycosaminoglycans and proteoglycans. These components provide structural support and flexibility to tissues.
In connective tissues, the ECM fills the space between cells and determines the physical characteristics of different tissues—such as the elasticity of the skin, the tensile strength of tendons, the flexibility of cartilage, and the structural support of bones. Normally, fibroblasts remain in a resting state but become activated in response to stimuli like wounds, infections, or inflammation. Under the influence of cytokines and transforming growth factor-beta 1 (TGF-β1), fibroblasts are activated, proliferate rapidly, synthesize ECM components, repair damaged tissue through fibrosis, regulate immune cell recruitment and inflammatory responses, and secrete growth factors and cytokines to promote tissue recovery.
Depending on the specialized function of the tissue, fibroblasts differentiate into various forms and are referred to by different names. Examples include dermal fibroblasts that produce collagen and elastin in the dermis to maintain skin elasticity and moisture; pulmonary fibroblasts that manage the elasticity and regeneration of alveolar tissues in the lungs; synovial fibroblasts that produce components of synovial fluid to reduce joint friction; and cardiac fibroblasts that support cardiac muscle contraction and repair damaged heart tissue.
Collagen Fibers and Braiding Straw Ropes
While studying the collagen biosynthesis process, I was reminded of the traditional craft of braiding straw ropes. I’m not sure if I saw it in a movie or a documentary, but I recall a scene of people sitting in a warm room on a cold winter day, twisting straw between their palms to make thin ropes, then braiding those into thicker ropes. These ropes would then be used to make straw shoes, mats, or baskets. The collagen biosynthesis process is quite similar. Initially, long and thin amino acid chains are synthesized, like strands of straw. Then, three of these chains twist together to form a triple helix, reminiscent of a braided rope. When dozens or hundreds of these helices align in parallel, they form fibrils, which then bundle together to form collagen fibers. Just as weak straw becomes strong rope and that rope becomes a sturdy, flexible mat or basket, collagen fibers interweave to form the solid foundation of connective tissues.
The Process of Collagen Biosynthesis
Collagen gene transcription begins in the nucleus. This is translated by ribosomes into long polypeptides known as α-chains. In these linear chains, the smallest amino acid, glycine, appears every third residue. This repetitive structure likely allows the three chains to twist tightly into a stable helix. At this stage, the structure is referred to as a pre-pro-peptide—an indication that much transformation lies ahead.
Each α-chain has a signal peptide at its N-terminus, guiding it from the ribosome into the lumen of the rough endoplasmic reticulum (ER). Once inside, the signal peptide is removed, and the chain becomes a pro-peptide. Before the three α-chains can form a triple helix, they must undergo post-translational modifications.
First, proline and lysine residues within the chains are hydroxylated—hydroxylation adds OH groups. Hydroxyproline forms hydrogen bonds between chains, stabilizing the helix. Hydroxylysine is essential for later cross-linking between collagen molecules, a prerequisite for forming stable fibrils. These strong cross-links give collagen its tensile strength. Hydroxylysine may also undergo glycosylation—attachment of glucose or galactose—which modulates collagen’s later functions.
There is one very important factor we need to pay attention. vitamin C acts as an essential cofactor for the hydroxylase enzymes required for hydroxylation. No matter how much collagen you consume, if you are deficient in vitamin C, collagen synthesis will not proceed properly.
During these modifications, each α-chain folds into a left-handed helix. Two α1-chains and one α2-chain then assemble to form pro-collagen. Starting at the C-terminal end, the three chains zip together into a right-handed triple helix (superhelix), stabilized by disulfide bonds. This procollagen is transported from the ER to the Golgi apparatus and then secreted outside the cell.
Once in the extracellular matrix, the telopeptides (the disulfide-rich ends) are cleaved by enzymes. This is akin to trimming the ends of a roll. The resulting structure is called tropocollagen. Tropocollagen molecules align and bind to form small fibrils. Thanks to the earlier hydroxylation of lysine, stable cross-links form between tropocollagen molecules, enabling fibril formation.
Tropocollagen molecules arrange in a staggered fashion, with overlapping and non-overlapping regions. This uneven electron density gives rise to periodic light and dark banding patterns observable under electron microscopy—a feature we previously discussed in bone formation.
Thousands of these fine fibrils gather to form large, thick collagen fiber bundles, which can be compared to spools of thread or braided straw mats.
Collagen Composition in the Dermis Layer of Skin
Depending on the density and arrangement of fibrous proteins like collagen within the ECM, connective tissue can be categorized as loose or dense. Loose connective tissue contains fewer collagen fibers and is filled with water, immune cells, fat cells, and fibroblasts. It also has abundant blood vessels and nerves, forming a gel-like, soft matrix that facilitates the exchange of nutrients and metabolites. Examples include the lower dermis of the skin and the epithelial sublayer of the small intestine.
In contrast, dense connective tissue contains tightly packed collagen fibers, forming a rigid structure with high tensile strength. Tendons and ligaments fall into this category. Bones take this one step further—beyond dense connective tissue—by filling the tightly packed collagen spaces with minerals, forming a highly mineralized and compact matrix. The diagram shows the various collagen components in the dermal layer, a form of loose connective tissue. The keratinocytes in the epidermis cooperate with integrins and laminins to form a basement membrane that connects to the dermis. Just below the basement membrane, collagen is more loosely arranged.
Dietary Intake for Collagen Production
Collagen is synthesized within the body, so its building blocks and cofactors must be adequately supplied. Essential nutrients include amino acids such as glycine, cofactors like vitamin C needed for hydroxylation, and minerals like copper (Cu), zinc (Zn), and iron (Fe) that aid in forming stable collagen cross-links. These can be obtained through a balanced diet and used by the body to synthesize collagen. In situations where nutrient absorption is compromised or higher demand exists, collagen peptides can also be supplemented.
