The human skeleton undergoes constant remodeling throughout the lifetime. Processes occurring on microscopic and molecular scales degrade bone and replace it with new, fully functional tissue. Multiple bone remodeling events occur simultaneously, continuously and independently throughout the body, so that the entire skeleton is completely renewed about every ten years.Bone remodeling is performed by groups of cells called Bone Multicellular Units (BMU). BMUs consist of different cell types, some specialized in the resorption of old bone, others encharged with producing new bone to replace the former. These processes are tightly regulated so that the amount of new bone produced is in perfect equilibrium with that of old bone removed, thus maintaining bone microscopic structure.To date, many regulatory molecules involved in bone remodeling have been identified, but the precise mechanism of BMU operation remains to be fully elucidated. Given the complexity of the signaling pathways already known, one may question whether such complexity is an inherent requirement of the process or whether some subset of the multiple constituents could fulfill the essential role, leaving functional redundancy to serve an alternative safety role. We propose in this work a minimal model of BMU function that involves a limited number of signals able to account for fully functional BMU operation. Our main assumptions were i) at any given time, any cell within a BMU can select only one among a limited choice of decisions, i.e. divide, die, migrate or differentiate, ii) this decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor are coupled to that of specific external mediators, such as hormones, cytokines, growth factors. It was thus shown that efficient BMU operation manifests as an emergent process, which results from the individual and collective decisions taken by cells within the BMU unit in the absence of any external planning.

In situ hybridization studies allowed for the localization of three MMPs and the angiogenic factor VEGF during secondary ossification. MMPs were widely expressed during ossification of the secondary center, whereas expression of VEGF was restricted to later stages. Introduction: The spatiotemporal expression patterns of the matrix metalloproteinases gelatinase‐B (MMP‐9), collagenase‐3 (MMP‐13), and membrane‐type 1 metalloproteinase (MMP‐14) and the angiogenic peptide vascular endothelial growth factor (VEGF) were studied during development of the proximal epiphysis of the rat tibia. Materials and Methods: Cell expression was analyzed by in situ hybridization. Studies on osteoclastic activity, matrix mineralization, cell proliferation, and vascular progression were also performed. Results: MMP‐9, MMP‐13, and MMP‐14 were expressed in discrete perichondrial cells that gave way to sites of intrachondral canal formation. High expression levels for the three MMPs were found at the blind ends of advancing intrachondral canals and at the expanding borders of the marrow space. Signals for MMP‐9 and MMP‐13 were in close proximity but did not overlap, whereas MMP‐14 was expressed in both MMP‐9⁺ and MMP‐13⁺ cells. VEGF was not expressed during formation of intrachondral vascular canals but was observed in hypertrophic chondrocytes during formation of the bone marrow cavity. Conclusions: Expression of MMPs and VEGF are constant events during development of the secondary ossification center. We propose that MMPs are involved in targeting proteolytic activity during epiphyseal development. VEGF is not expressed during early formation of vascular canals, but it may have a role in the formation of the bone marrow cavity.

Our skeleton is an essential part of our body consisting of 206 pieces made of a specialized form of connective tissue, with a matrix containing collagen fibers and a large amount of minerals

The formation of the epiphyseal bone plate, the flat bony structure that provides strength and firmness to the growth plate cartilage, was studied in the present study by using light, confocal, and scanning electron microscopy. Results obtained evidenced that this bone tissue is generated by the replacement of the lower portion of the epiphyseal cartilage. However, this process differs considerably from the usual bone tissue formation through endochondral ossification. Osteoblasts deposit bone matrix on remnants of mineralized cartilage matrix that serve as a scaffold, but also on non-mineralized cartilage surfaces and as well as within the perivascular space. These processes occur simultaneously at sites located close to each other, so that, a core of the sheet of bone is established very quickly. Subsequently, thickening and reshaping occurs by appositional growth to generate a dense parallel-fibered bone structurally intermediate between woven and lamellar bone. All these processes occur in close relationship with a cartilage but most of the bone tissue is generated in a manner that may be considered as intramembranous-like. Overall, the findings here reported provide for the first time an accurate description of the tissues and events involved in the formation of the epiphyseal bone plate and gives insight into the complex cellular events underlying bone formation at different sites on the skeleton.

While the flat bones of the face, most of the cranial bones, and the clavicles are formed directly from sheets of undifferentiated mesenchymal cells, most bones in the human body are first formed as cartilage templates. Cartilage is subsequently replaced by bone via a very tightly regulated process termed endochondral ossification, which is led by chondrocytes of the growth plate (GP). This process requires continuous communication between chondrocytes and invading cell populations, including osteoblasts, osteoclasts, and vascular cells. A deeper understanding of these signaling pathways is crucial not only for normal skeletal growth and maturation but also for their potential relevance to pathophysiological processes in bones and joints. Due to limited information on the communication between chondrocytes and other cell types in developing bones, this review examines the current knowledge of how interactions between chondrocytes and bone-forming cells modulate bone growth.