Bone Repair

Cartilage Models - The Foundations

Cartilage - although having a very different in composition from bone (see Figure 1) - forms a tightly-controlled partnership with bone, on which formation of the latter relies.  Many bones, especially long bones in the limb and trunk, but not membrane bones of the skull, are built using a cartilage model as a foundation.  In fact, the cartilage model, which is developed in the embryo, can be thought of as a scale-down model of the bone which is to be formed.  The scale model, no more than a few millimeters long, grows with the embryo; new cartilage is formed and older cartilgae is replaced with bone (see Osteogenesis: Osteoblasts and Osteoclasts).  Endochrondal bone formation, the process by which the cartilage model is formed, begins with the condensation of embryonic connective tissue that then starts to express, among others, the Sox9 and Runx2 genes. 

Photographs to show the very different structures between cartilage and bone.

Figure 1 - (A) cartilage structure showing chrondocytes surrounded by freshly-secreted matrix, which mainly consists of proteoglycans and type II collagen. (B) bone structure showing type I collagen fibrils and hydroxylapatite crystals which resist pulling and compressive forces respectively.  Courtesy of R.M. Hunt (https://en.wikipedia.org/wiki/File:Hypertrophic_Zone_of_Epiphyseal_Plate.jpg and https://en.wikipedia.org/wiki/File:Woven_bone_matrix.jpg).

 

Sox9 expression leads to cells at the core of the condensation doing three things: (1) dividing, (2) enlarging, and (3), secreting a cartilaginous matrix.  This leads to formation of a cartilage "rod" surrounded by non-cartilaginous cells.  Cells at the centre of the "rod" secrete Indian Hedgehog (Ihh) which leads to activation of the Wnt pathway in the surrounding cells.  Sox9 expression is then repressed, but Runx2 expression is maintained, and this leads to osteoblast differentiation of these cells.  The process so far is summarised in Figure 2 and its accompanying text.

 

a summary of endochrondal bone formation. Sox9 induces cartilage matrix secretion. Indian hedgehog activates the Wnt pathway and switches off Sox9, allowing Runx2 to induce osteoblast differentiation.

 Figure 2 - summary of endochrondal bone formation, leading to osteoblast differentiation.  Sox9 expression leads to the secretion of cartilage matrix from a condensation of embryonic connective tissue cells, which enlarge and divide as they do so, forming a "rod".  The cells at the centre of the rod secrete Indian Hedgehog (Ihh) which activates the Wnt pathway via production of Wnt proteins, switching off Sox9 expression and allowing Runx2 expression to prevail.  This leads to osteoblast differentiation around the cartilage "rod".    

 

The cartilage cells in the "rod" of the model then die, leaving behind cavities.  Several processes then occur:

  • The matrix surrounding the cavities is mineralised by hydroxylapatite crystal deposition. 
  • Osteoclasts (described below) erode any remaining cartilage matrix which has not been mineralised.
  • Osteoblasts start to deposit trabecular bone (criss-cross patterns of bone tissue)
  • Bone marrow starts to fill cavities left from death of cartilage cells and erosion of cartilage matrix.

 Osteoclast and osteoblast cells are now responsible for the remainder of the bone formation process, and their roles will now be considered.

.  Continue to: Osteogenesis: Osteoclasts & Osteoblasts