The skeleton's construction workers are cells known as osteoblasts. A little-known protein called Osteopotentia helps these cells grow up and produce strong bones, Sohaskey et al. show (1).
Osteoblasts pump out type I collagen, the protein that accounts for almost all the non-mineral content of bone (2). “The main point of being an osteoblast is to make collagen,” says lead author Mike Sohaskey, a postdoc in the lab of Richard Harland. As they are synthesized, type I collagen molecules feed into the rough endoplasmic reticulum (ER), where they are modified and folded into shape (3). The osteoblast then secretes the proteins for further processing and assembly into fibrils, the functional units of collagen.
Bone construction surges before birth and during childhood. During this period, osteoblasts amass additional rough ER to cope with their increased collagen output. How the cells manage these changes isn't known, but the protein Osteopotentia could be involved because its loss disrupts skeletal growth (4).
Sohaskey et al. studied mice with a disabled osteopotentia gene. Bone building falters in osteogenesis imperfecta (OI), a rare disease characterized by a brittle, fracture-prone skeleton. The phenotype of mice lacking a working copy of the osteopotentia gene resembled that of OI patients in several ways. They were smaller than normal, and their bones were thin and snapped easily.
“This gives us a whole new perspective on a pathway responsible for bone formation.”
The problem was a case of arrested development: without Osteopotentia, many immature osteoblasts didn't grow up. Reflecting their immaturity, cultures of the cells fashioned up to 80% less type I collagen than normal. Some of the osteoblasts even morphed into osteocytes, a cell type that produces little bone.
Osteoblasts partner with osteoclasts—cells that demolish bone—to fine-tune the strength of the skeleton (5). Overactive osteoclasts could explain the animals’ fragile bones. But, to their surprise, Sohaskey et al. discovered that the rodents harbored sluggish osteoclasts. So although the animals create less bone than normal, they also dissolve less.
Where Osteopotentia settled had been a mystery, but the team traced the protein to the rough ER—the right place to alter collagen synthesis. The protein enables the cell to expand the rough ER and meet the need for more collagen. In cells lacking Osteopotentia, the organelle's membranes were small and fragmented.
The findings suggest that Osteopotentia is a triple threat, controlling collagen production, rough ER size, and osteoblast maturation. “This gives us a whole new perspective on a pathway responsible for bone formation,” says Sohaskey. He speculates that in the mice lacking Osteopotentia, problems start early in life, when collagen demand climbs. But osteoblasts manufacture little collagen. That scarcity holds back the cells because they require surroundings that are rich in the protein to mature. The end result is a fragile skeleton.
How Osteopotentia affects ER structure is one open question. Sohaskey et al. also want to determine whether faulty Osteopotentia is the culprit in any human diseases. OI patients typically carry a mutation in one of the two collagen genes. But both genes are normal in some sufferers, suggesting that other genetic glitches can trigger the disease. In the team's preliminary study of OI patients, none had a defective osteopotentia gene, but the researchers plan to check for mutations in a broader range of patients.