**5. Remodeling**

Remodeling proceeds in consequence of osteolysis and forthcoming osteogenesis. In the beginning, a group of activated osteoclasts, acidifying ECM, dissolve the osteoid and enzymatically (MMPs) digest its proteins. In consequence, resorptive (Howship) lacuna is formed.

Released molecules that are stored in the latent form bound to ECM heparan sulfate (BMPs, Vascular endothelial growth factor (VEGF), FGF, and EGF) activate proliferation and folding into three-dimensional structures of endothelial cells originating from neighboring blood vessels [30]. Those form vascular loops (sprouts) in-growing into the lacunae, providing its blood supply. Inflowing MSCs differentiate into osteoblasts that repopulate lacunae as osteocytes excreting ECM proteins and mineralizing them.

Osteoclasts at the top (cutting cone) gradually move across the bone as far as they reach its borderline (osteoclastic tunneling; remaining as Haversian canal), and finally undergo apoptosis. Passing across the fracture, they restore bone continuity (osteonal fracture healing), but only when the distance between bone fragments does not exceed 1 mm [31]. If the distance is higher, each bone fragment is remodeled alone and the fracture gap remains intact, that is not healed.
