Age-Related Changes in the Mechanical Regulation of Bone Healing Are Explained by Altered Cellular Mechanoresponse

Abstract

Increasing age is associated with a reduced bone regeneration potential and increased risk of morbidities and mortality. A reduced bone formation response to mechanical loading has been shown with aging, and it remains unknown if the interplay between aging and mechanical stimuli during regeneration is similar to adaptation. We used a combined in vivo/in silico approach to investigate age-related alterations in the mechanical regulation of bone healing and identified the relative impact of altered cellular function on tissue patterns during the regenerative cascade. To modulate the mechanical environment, femoral osteotomies in adult and elderly mice were stabilized using either a rigid or a semirigid external fixator, and the course of healing was evaluated using histomorphometric and micro-CT analyses at 7, 14, and 21 days post-surgery. Computer models were developed to investigate the influence of the local mechanical environment within the callus on tissue formation patterns. The models aimed to identify the key processes at the cellular level that alter the mechanical regulation of healing with aging. Fifteen age-related biological alterations were investigated on two levels (adult and elderly) with a design of experiments setup. We show a reduced response to changes in fixation stability with age, which could be explained by reduced cellular mechanoresponse, simulated as alteration of the ranges of mechanical stimuli driving mesenchymal stem cell differentiation. Cellular mechanoresponse has been so far widely ignored as a therapeutic target in aged patients. Our data hint to mechanotherapeutics as a potential treatment to enhance bone healing in the elderly. Fig. 1. Finite element models of the mice femoral osteotomy stabilized with a rigid (A) and a semirigid fixator (B) and predicted compressive principal strain distributions within the callus. Callus regions under investigation and their dimensions are reported. Ps = periosteal; I = intracortical; Es = endosteal. [Color figure can be viewed at wileyonlinelibrary.com] Journal of Bone and Mineral Research AGE-RELATED ALTERED CELLULAR MECHANORESPONSE IN BONE HEALING 1925 ■ 30. Willie BM, Birkhold AI, Razi H, et al. Diminished response to in vivo mechanical loading in trabecular and not cortical bone in ◼ 14 BORGIANI ET AL.

Evaluation of longitudinal time-lapsedin vivomicro-CT for monitoring fracture healing in mouse femur defect models

“…Specifically, we saw that the initiation of bone formation (maximum in week 2-3), indicating the onset of the reparative phase, triggered bone resorption (maximum in week 3-4) with maximum osseous callus volumes in week 3. These observations are in line with cross-sectional histomorphometric analyses in similar defect models, where maximum callus area was seen in weeks 2 and 3 37–39 . From week 4 to week 6, bone formation and resorption continuously decreased to levels (BFR ≤ 1%/day; BRR ≤ 0.8%/day) seen in normal bone remodeling of trabecular and cortical bone in mice 14,40–43 , indicating proceeding towards the end of the healing process.…”

“…These commercially available rigid external fixators are widely used in fracture healing studies as they also allow for the assessment of biomaterials in non-union defects (induced by increasing the defect size). Borgiani et al 37 have recently extensively characterized the healing process (week 1-3) using external fixators of similar stiffness and observed endochondral ossification processes, albeit less pronounced compared to semi-rigid fixation. When comparing the outcome of these studies using rigid fixation, it is important to consider differences in defect sizes: 0.7mm 2 , 1.19±0.25 mm 44 , 1.47±0.16mm (this study).…”

Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels

“…Bone healing is a spatiotemporally regulated regeneration process, ideally leading to complete restoration of the broken bone without fibrous scar formation (1). Naturally, this regeneration process undergoes endochondral bone formation, if interfragmentary movements strain the fracture gap (2). In the majority of clinical cases, fracture healing follows the endochondral route and may be sub-divided into five phases, namely an (i) initial pro-inflammatory phase, (ii) antiinflammatory phase, (iii) fibrocartilaginous or soft callus phase, (iv) mineralization or hard callus phase and (v) remodeling phase in which bone tissue regains its physiological shape with a restored bone marrow cavity.…”

Multiscale Modeling of Bone Healing: Toward a Systems Biology Approach

“…Using this approach, Checa et al (2011) and Borgiani et al (2015) showed that differences in the healing pattern (e.g., endosteal, periosteal, time to bringing) of different species (sheep, rat, and mice) can be explained by differences in the regulation of cellular activity by mechanical signals during the course of healing.…”