The turnover of mineralized growth plate cartilage into bone may be regulated by osteocytes

Abstract

During endochondral ossification, growth plate cartilage is replaced with bone. Mineralized cartilage matrix is resorbed by osteoclasts, and new bone tissue is formed by osteoblasts. As mineralized cartilage does not contain any cells, it is unclear how this process is regulated. We hypothesize that, in analogy with bone remodeling, osteoclast and osteoblast activity are regulated by osteocytes, in response to mechanical loading. Since the cartilage does not contain osteocytes, this means that cartilage turnover during endochondral ossification would be regulated by the adjacent bone tissue. We investigated this hypothesis with an established computational bone adaptation model. In this model, osteocytes stimulate osteoblastic bone formation in response to the mechanical bone tissue loading. Osteoclasts resorb bone near randomly occurring microcracks that are assumed to block osteocyte signals. We used finite element modeling to evaluate our hypothesis in a 2D-domain representing part of the growth plate and adjacent bone. Cartilage was added at a constant physiological rate to simulate growth. Simulations showed that osteocyte signals from neighboring bone were sufficient for successful cartilage turnover, since equilibrium between cartilage remodeling and growth was obtained. Furthermore, there was good agreement between simulated bone structures and rat tibia histology, and the development of the trabecular architecture resembled that of infant long bones. Additionally, prohibiting osteoclast invasion resulted in thickened mineralized cartilage, similar to observations in a knock-out mouse model. We therefore conclude that it is well possible that osteocytes regulate the turnover of mineralized growth plate cartilage.

A sclerostin-based theory for strain-induced bone formation

“…The stimulatory model predicts little bone formation in such cases, whereas the inhibitory model predicts the exact opposite. Recently, Cox et al (2011) used computer simulations based on the stimulatory model to study the replacement of calcified cartilage by bone under the growth plate. They found that osteocytes at the bone-cartilage interface were able to facilitate this turnover via the stimulatory pathway.…”

Alterations to the subchondral bone architecture during osteoarthritis: bone adaptation vs endochondral bone formation

“…In a previous study we showed that the replacement of mineralized cartilage with bone tissue can also be simulated with the model 31 . Cartilage was successfully replaced with bone, and there was good agreement between simulation results and experimental data from the literature 32,33 .…”

“…This resorption rule was based on literature reports that mineralized cartilage resorption is the result of osteoclast precursor delivery by blood vessels that penetrate the mineralized cartilage 32 . After cartilage resorption, bone formation was assumed to be regulated by mechanosensing osteocytes, similar to bone formation during adaptation 31 .…”