Cellular basis for age-related changes in fracture repair

Abstract

The goal of this work was to define cellular and molecular changes that occur during fracture healing as animals age. We compared the molecular, cellular, and histological progression of skeletal repair in juvenile (4 weeks old), middle-aged (6 months old), and elderly (18 months old) mice at 3, 5, 7, 10, 14,21,28, and 35 days post-fracture, using a non-stabilized tibia fracturqmodel. Our histological and molecular analyses demonstrated that there was a sharp decline in fracture healing potential between juvenile and middle-aged animals, while a more subtle decrease in healing potential was apparent between middle-aged and elderly mice. By three days after fracture, chondrocytes expressing Collagen type ZZ, and osteoblasts expressing osteocalcin, were present in calluses of juvenile, but not middle-aged or elderly, mice. At day 5 immature chondrocytes and osteoblasts were observed in calluses of middle-aged and elderly mice. While at this time, chondrocytes in juvenile mice were expressing Collagen type X (ColX) indicating that chondrocyte maturation was already underway. At day 7, chondrocytes expressing ColX were abundant in middle-aged mice while a small domain of ColX-positive chondrocytes were observed in elderly mice. Further, in juvenile and middle-aged mice, but not elderly mice, vascular invasion of the cartilage was underway by day 7. Juvenile mice had replaced nearly all of the cartilage by day 14, while cartilage was still present in the callus of middle-aged mice at day 21 and in elderly mice at day 28. In addition to these delays, histomorphometry revealed that elderly and middle-aged mice formed less bone than juveniles (p < 0.001), while cartilage production was unaffected (p > 0.22). Collectively, these data suggest that enhancing cell differentiation, improving osteoblast function, and accelerating endochondral ossification may significantly benefit the elderly.

Delayed Bone Regeneration Is Linked to Chronic Inflammation in Murine Muscular Dystrophy

“…Serial 10‐µm longitudinal sections were collected throughout the entire callus tissue using a Leica microtome (Leica Microsystems GmbH, Wetzler, Germany). To compare fracture repair rates between mdx and wild‐type mice, histomorphometric analyses of total callus, cartilage, and trabecular bone volumes were performed via Adobe PhotoShop (Adobe, Inc., San Jose, CA, USA) as described in Colnot and colleagues and Lu and colleagues . A minimum of seven equidistant sections spaced at 300 µm apart throughout the callus was evaluated.…”

Review of Animal Models of Comorbidities in Fracture‐Healing Research

“…Physiological changes associated with ageing have a great effect on vascularization and angiogenesis during fracture healing . Lu et al observed juvenile (4 weeks), middle‐aged (6 months) and elderly (18 months) mice, with non‐stabilized tibia fractures, and compared cellular, molecular and histological progression of fracture repair. Results indicated decreased bone formation, impaired bone remodeling, delayed angiogenic invasion of cartilage, prolonged endochondral ossification and delays in cell differentiation associated with aging.…”

A Surgical Procedure for Resecting the Mouse Rib: A Model for Large-Scale Long Bone Repair

“…Although the flanking ribs provide sufficient stability around the resection such that no external fixator is needed, the repair zone is under the constant movement and strain of lung inflation/deflation. It has been recognized that during bone repair, too much movement can be inhibitory to healing while some movement appears to be important for generating a cartilage intermediate 13,14 . At this point, it is not clear, however it is possible that formation of a cartilage intermediate may be a key step for effective large-scale repair.…”