How Fibrodysplasia Ossificans Progressiva (FOP) Works

FOP Bone versus Normal Bone

Bone is a living tissue. Each bone in your body is an organ, made up of tissues and cartilage. FOP bone is just like normal bone -- it's just in the wrong place.

Ossification and osteogenesis are words for bone formation. There are two methods of bone formation: intramembranous and endochondral. Intramembranous bone formation is the simpler process, and it's responsible for forming a person's skull and lower jawbone. It's also how long bones like the humerus and femur grow in width.

Most bones in the body grow and heal after a break through endochondral bone formation. It's also how FOP bone grows. First, cartilage forms, and then bone gradually takes the place of the cartilage.

Both kinds of ossification begin with mesenchyme. Mesenchyme is a connective tissue that all other connective tissues come from. Mesenchymal cells can turn into different kinds of specialized cells that form tissues. Here is how the process of endochondral bone formation works:

  1. Mesenchymal cells come together in the shape of the bone they will form. They turn into chondroblasts -- cells that secrete cartilage matrix. A membrane called the perichondrium surrounds this cartilage.
  2. After the chondroblasts cover themselves in cartilage matrix, they turn into chondrocytes. The chondrocytes keep dividing while new chondroblasts continue to make cartilage matrix, causing the cartilage to grow.
  3. Some of the chondrocytes burst, and others die. The bursting of the cells causes calcification, or hardening of the cartilage. The dying cells make small spaces in the cartilage.
  4. A nutrient artery enters the cartilage, triggering cells in the perichondrium to turn into osteoblasts. Osteoblasts are just like chondroblasts, but they secrete bone matrix instead of cartilage matrix. The osteoblasts start to secrete compact bone, and the perichondrium becomes the periosteum -- the covering of the outside of the bone.
  5. Blood vessels grow into the cartilage and bring red bone marrow cells and other bone cells with them. The blood vessels stimulate a primary ossification center to grow -- this is the place where bone tissue will begin to take the place of cartilage. Osteoblasts start covering the broken-down cartilage with bone matrix.
  6. Osteoclasts follow behind the osteoblasts and break down the spongy bone, making a cavity for red bone marrow to fill.

At this point, the long part of the bone, which started as cartilage, is compact bone with red bone marrow in the center. The endochondral bone formation finishes with the epiphyses, the ends of the bones. Secondary ossification centers develop to form bone, although unlike with the primary ossification center, spongy bone stays at the center of epiphyses instead of marrow.

This process uses undifferentiated cells, or cells that can grow into any type of cell, to make bones. The amazing thing about FOP is that the body convinces undifferentiated cells in tendons, ligaments and muscles to turn into something completely different. The body doesn't normally work this way. With FOP, ligaments and tendons and other connective tissues all go through this process of bone formation. It's normal bone, but in the wrong place at the wrong time. This is called heterotopic ossification.

In FOP patients, extra bone formation almost always starts at the neck, spine and shoulders. Only then does it move to the other joints.

So what happens with FOP? A mutation in the gene encoding activin receptor IA (ACVR1) tells the body to make an extra skeleton. This gene helps control bone morphogenetic proteins, or BMPs. In FOP, the gene is active without BMPs -- operating like a leaky faucet. When BMPs are present, the faucet explodes with activity. This clue might someday help scientists figure out how to make extra bone for people who need it, like people with osteoporosis.

­In the next section, we'll learn ho­w doctors treat FOP.