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 fracture model. 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 II, 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.

Accelerated fracture healing in the geriatric, osteoporotic rat with recombinant human platelet‐derived growth factor‐bb and an injectable beta‐tricalcium phosphate/collagen matrix

“…Geriatric and osteoporotic patients may have a different biological potential for wound healing than nongeriatric, nonosteoporotic patients based on preclinical studies suggesting a reduction in lineage progression and proliferative activity of osteoblast progenitor cells and gene expression, a decrease in osteoblast function, diminished osteoblast response to signaling cues, and an imbalance between the coupling of bone formation and resorption. 2,[4][5][6][7][8]11,22,29,30 Therefore, the biological properties of rhPDGF-BB may be an important therapeutic consideration for geriatric and osteoporotic patients.…”

“…[1][2][3] In the osteoporotic and elderly, there is a reduction in lineage progression [4][5][6] and proliferative activity of osteoblast progenitor cells and gene expression, 7 a decrease in osteoblast function, 8 diminished osteoblast response to signaling cues, and an imbalance between the coupling of bone formation and resorption (reviewed 2 ). Consequently, bone healing in elderly and osteoporotic individuals may be delayed and new bone quality may be poor.…”

Ischemia leads to delayed union during fracture healing: A mouse model

“…10 Ischemic and control animals with nonstabilized fractures were sacrificed at 3 and 5 days postfracture (n ¼ 5/time for both ischemic and control groups). Fracture tissue was fixed in 4% paraformaldehyde (PFA), decalcified in 19% EDTA, and frozen sections of 20 mm were prepared.…”

“…Animals with non-stabilized fractures (n ¼ 5/time for both ischemic and control groups) were sacrificed at multiple time points post-injury (3,5,7,10,14,21, and 28 days) to assess the effect with ischemia on different aspects of fracture healing. Animals with stabilized fractures (n ¼ 5/ time for both ischemic and control groups) were sacrificed at 10 and 14 days post-fracture when the cartilage should be most abundant if there is an affect on chondrogenesis.…”

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing

“…We focused our assessments on days 10 and 28 because the peak of osteogenesis occurs between 10 to 14 days after fracture and because cartilage replacement with bone in the callus to bridge the fracture gap is usually completed by 28 days. (8,23) mCT imaging demonstrated that the bone fracture gap was bridged by bony tissue by day 28 ( Fig. 2A, Supporting Fig.…”