Two populations of cells work on maintaining bone tissue; osteoclasts break down bone, while osteoblasts build it up. There is a constant dynamic process of remodeling underway in which both cell populations participate. Unfortunately, the balance between creation and destruction runs awry in aging, with an ever greater deficit in the creation of bone tissue. This leads to a progressive loss in bone density and the development of osteoporosis: bones become ever more brittle and fragile. A number of existing and potential treatments attempt to override the activity of osteoclasts or osteoblasts, restoring the balance without addressing the root causes of the change. Here, researchers use modeling to propose that one such treatment could in theory be used to restore the bones of osteoporosis patients to a healthy density. The proof of that remains to be accomplished, however.
They may seem rigid and set in their ways, but your bones are actually under constant construction and deconstruction. They give up their nutrient treasures (calcium) to the body and then rebuild in a constant give-and-take sort of rhythm. When that rhythm shifts with advancing age or the onset of osteoporosis, the rebuilding process decreases. Bones lose density and strength and become more prone to fracture. Now researchers have applied mathematical modeling expertise to biological inquiry in order to point the way to a promising remedy. The biologist has shown that treating a mouse with a peptide known as CK2.3 increases bone mineral density. The mathematician has calculated estimated dosages for human beings. According to their model, injections of CK2.3 can raise bone mineral density of bones badly degraded by osteoporosis back to healthy levels.
Bone mineral density is affected by two processes: bone formation and bone degradation. Current drug treatments, especially bisphosphonates, address the cells involved in bone degradation (osteoclasts). Only the approved drug parathyroid hormone (PTH) addresses the cells involved in bone formation (osteoblasts) but doctors must prescribe bisphosphonates with it to target bone degradation simultaneously. The peptide used in this research - CK2.3 - is the only one that decreases bone degradation while simultaneously increasing bone formation.
One team designed the mimetic peptide CK2.3 and showed that it increased bone mineral density in a mouse model by blocking the CK2 protein's interaction with the BMPR1a protein - an interruption that allows the cells that form new bone (osteoblasts) to increase. Subcutaneous (below the skin) injection increased bone formation in the crown of the skull (known as calvaria), while systemic injection decreased bone degradation and increased bone mineral density. The other team used that information to calculate ideal dosages for healthy humans and those with osteoporosis. A mouse and a human are different in many ways, so calculating a dosage is more complex than just adjusting for differences in weight. Researchers developed part of the model using the concepts in physiology-based pharmacokinetic (PBPK) models. Such models can be used to calculate how a pharmaceutical molecule distributes in different parts of the body. In this case, the researchers needed to know what the local concentration of CK2.3 would be at the site where bone is formed. Once this was determined, another math model was used to calculate bone mineral density.