Final Report Summary - OSTEOMOTION (OsteoMotion: Analyzing the mechanisms and role of osteogenic cell movement in bone development and disease)
From a clinical, societal and economic point of view, one of the largest unmet needs in the bone field today relates to the development of novel, improved, safe and highly effective therapies to stimulate bone formation. These so-called osteo-anabolic therapies are needed to address the problem of the widespread and increasing prevalence of bone disorders such as (age-related) osteoporosis, which is characterized by low bone mass and increased risk of fractures, as well as to treat compromised fracture repair, by stimulating endogenous repair mechanisms or through bone tissue engineering strategies. The discovery of new osteo-anabolic angles and drug targets will depend on a comprehensive understanding of osteogenic cell biology and bone formation.
Mature, bone-forming osteoblasts anatomically positioned on the bone surfaces differentiate from mesenchymal progenitors residing in the stromal bone marrow environment. Indispensable aspects of bone formation, whether during development, remodeling or repair, accordingly include the recruitment and engagement of osteoprogenitors, their migration towards and attachment on the bone surface at sites in need of bone formation, and their proper differentiation and activation into functional, bone-forming osteoblasts. All these processes heavily depend on communication between the osteogenic cells and their surroundings, including the extracellular matrix (ECM), other cells, and the blood vessels of the bone and bone marrow environment, but the underlying mechanisms and molecular determinants are incompletely understood.
This project was designed to gain insights in several aspects related to osteoprogenitor movement and recruitment of osteogenic cells to sites of bone formation, which in preceding work was documented to occur in close interplay with skeletal vascularization processes. These aspects included (i) cell-matrix interactions and cell-autonomous mechanisms regulating osteoprogenitor migration, (ii) osteoblastic cell-cell adhesion, and (iii) regulatory mechanisms underlying the osteo-angiogenic coupling paradigm. In the first part of the project we took a candidate gene approach to assess the importance of selected mechanistic targets for each of these three sub-aspects. We thereby focused on osteoprogenitors and their osteoblast lineage progeny by generating conditional knockout (cKO) mice using the Osx-Cre:GFP mouse strain, and later in the project also the Prx1-Cre driver strain that targets the early mesenchymal progenitors that give rise to the limb bones. The results of these studies have led and are leading to new insights in basic osteoblast biology, bone formation, marrow adipose tissue development, the role of osteolineage cells in the integrative functioning of bone with regard to systemic glucose metabolism and hematopoiesis, and fracture healing.
In a second part of the project we took a different, unbiased molecular target approach. We therefore developed a methodology to selectively isolate specific cell (sub-)populations from their in vivo environment in developing mouse bones, and processed them for transcriptome screening in order to extend the search for interesting candidate molecules towards novel or unanticipated mechanisms and genes. This endeavor was successfully unfolded as originally envisioned, thus allowing us to go beyond the candidate gene strategy in future follow-up projects.
Altogether, the results of this project provide new insights in aspects of osteogenic cell biology and bone formation, and add to our broader understanding of skeletal health, disease and repair. Several promising lines of research that descend from these initial studies are subjects of ongoing investigations in our lab. The already achieved and additional expected basic insights into how healthy bones are built and maintained in adult life will contribute to the exposure of novel therapeutic targets for the future development of drugs that can stimulate bone formation in osteoporotic patients and in bone regeneration strategies.
Mature, bone-forming osteoblasts anatomically positioned on the bone surfaces differentiate from mesenchymal progenitors residing in the stromal bone marrow environment. Indispensable aspects of bone formation, whether during development, remodeling or repair, accordingly include the recruitment and engagement of osteoprogenitors, their migration towards and attachment on the bone surface at sites in need of bone formation, and their proper differentiation and activation into functional, bone-forming osteoblasts. All these processes heavily depend on communication between the osteogenic cells and their surroundings, including the extracellular matrix (ECM), other cells, and the blood vessels of the bone and bone marrow environment, but the underlying mechanisms and molecular determinants are incompletely understood.
This project was designed to gain insights in several aspects related to osteoprogenitor movement and recruitment of osteogenic cells to sites of bone formation, which in preceding work was documented to occur in close interplay with skeletal vascularization processes. These aspects included (i) cell-matrix interactions and cell-autonomous mechanisms regulating osteoprogenitor migration, (ii) osteoblastic cell-cell adhesion, and (iii) regulatory mechanisms underlying the osteo-angiogenic coupling paradigm. In the first part of the project we took a candidate gene approach to assess the importance of selected mechanistic targets for each of these three sub-aspects. We thereby focused on osteoprogenitors and their osteoblast lineage progeny by generating conditional knockout (cKO) mice using the Osx-Cre:GFP mouse strain, and later in the project also the Prx1-Cre driver strain that targets the early mesenchymal progenitors that give rise to the limb bones. The results of these studies have led and are leading to new insights in basic osteoblast biology, bone formation, marrow adipose tissue development, the role of osteolineage cells in the integrative functioning of bone with regard to systemic glucose metabolism and hematopoiesis, and fracture healing.
In a second part of the project we took a different, unbiased molecular target approach. We therefore developed a methodology to selectively isolate specific cell (sub-)populations from their in vivo environment in developing mouse bones, and processed them for transcriptome screening in order to extend the search for interesting candidate molecules towards novel or unanticipated mechanisms and genes. This endeavor was successfully unfolded as originally envisioned, thus allowing us to go beyond the candidate gene strategy in future follow-up projects.
Altogether, the results of this project provide new insights in aspects of osteogenic cell biology and bone formation, and add to our broader understanding of skeletal health, disease and repair. Several promising lines of research that descend from these initial studies are subjects of ongoing investigations in our lab. The already achieved and additional expected basic insights into how healthy bones are built and maintained in adult life will contribute to the exposure of novel therapeutic targets for the future development of drugs that can stimulate bone formation in osteoporotic patients and in bone regeneration strategies.