Microdamage in bone: implications for fracture, repair, remodeling, and adaptation.

Fatigue microdamage accumulates in bone as a result of physiological loading. The damage is often manifested as microcracks, which are typically 50-100 mum long. These types of cracks develop in the interstitial bone and frequently abut osteon cement lines. In vitro experimentation has shown that an accumulation of fatigue damage reduces the material properties of bone (e.g., elastic modulus). An accumulation of fatigue damage has been implicated in the etiology of stress fractures and fragility fractures. However, bone has a remarkable ability to detect and repair fatigue microdamage. This article reviews the experimental techniques for identifying and quantifying different types of microdamage in bone, the density of in vivo microcracks at different skeletal locations, the effect of microdamage on bone material properties, the role of microdamage in bone fracture, and the biological mechanisms for the detection and repair of fatigue microdamage.

A fatigue microcrack alters fluid velocities in a computational model of interstitial fluid flow in cortical bone.

Targeted remodeling is activated by fatigue microcracks and plays an important role in maintaining bone integrity. It is widely believed that fluid flow-induced shear stress plays a major role in modulating the mechanotransduction process. Therefore, it is likely that fluid flow-induced shear stress plays a major role in the initiation of the repair of fatigue damage. Since no in vivo measurements of fluid flow within bone exist, computational and mathematical models must be employed to investigate the fluid flow field and the shear stress occurring within cortical bone. We developed a computational fluid dynamic model of cortical bone to examine the effect of a fatigue microcrack on the fluid flow field. Our results indicate that there are alterations in the fluid flow field as far as 150 microm away from the crack, and that at distances farther than this, the fluid flow field is similar to the fluid flow field of intact bone. Through the crack and immediately above and below it, the fluid velocity is higher, while at the lateral edges it is lower than that calculated for the intact model, with a maximum change of 29%. Our results suggest that the presence of a fatigue microcrack can alter the shear stress in regions near the crack. These alterations in shear stress have the potential to significantly alter mechanotransduction and may play a role in the initiation of the repair of fatigue microcracks.

T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling.

Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis because it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here, we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells and induces these lymphocytes to activate canonical Wnt signaling in preosteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in preosteoblasts and blunted osteoblastic commitment, proliferation, differentiation, and life span, which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wnt10b, iPTH has no anabolic activity in mice lacking T-cell-produced Wnt10b. Therefore, T-cell-mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast crosstalk pathways may provide pharmacological targets for bone anabolism.

T cells potentiate PTH-induced cortical bone loss through CD40L signaling.

Parathyroid hormone (PTH) promotes bone catabolism by targeting bone marrow (BM) stromal cells (SCs) and their osteoblastic progeny. Here we show that a continuous infusion of PTH that mimics hyperparathyroidism fails to induce osteoclast formation, bone resorption, and cortical bone loss in mice lacking T cells. T cells provide proliferative and survival cues to SCs and sensitize SCs to PTH through CD40 ligand (CD40L), a surface molecule of activated T cells that induces CD40 signaling in SCs. As a result, deletion of T cells or T cell-expressed CD40L blunts the bone catabolic activity of PTH by decreasing bone marrow SC number, the receptor activator of nuclear factor-kappaB ligand (RANKL)/OSTEOPROTEGERN (OPG) ratio, and osteoclastogenic activity. Therefore, T cells play an essential permissive role in hyperparathyroidism as they influence SC proliferation, life span, and function through CD40L. T cell-SC crosstalk pathways may thus provide pharmacological targets for PTH-induced bone disease.

Parathyroid hormone may maintain bone formation in hibernating black bears (Ursus americanus) to prevent disuse osteoporosis.

Mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears (Ursus americanus) are inactive for up to six months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. To test whether hibernating bears have biological mechanisms to prevent disuse osteoporosis, we measured the serum concentrations of hormones and growth factors involved in bone metabolism and correlated them with the serum concentration of a bone formation marker (osteocalcin). Serum was obtained from black bears over a 7-month duration that included periods of activity and inactivity. Both resorption and formation markers increased during hibernation, suggesting high bone turnover occurred during inactivity. However, bone formation appeared to be balanced with bone resorption. The serum concentration of parathyroid hormone (PTH) was higher in the hibernation (P=0.35) and post-hibernation (P=0.006) seasons relative to pre-hibernation levels. Serum leptin was lower (P<0.004) post-hibernation relative to pre-hibernation and hibernation periods. Insulin-like growth factor I (IGF-I) decreased (P<0.0001) during hibernation relative to pre-hibernation and reached its highest value during remobilization. There was no difference (P=0.64) in 25-OH vitamin D between the three seasons. Serum osteocalcin (bone formation marker) was significantly correlated with PTH, but not with leptin, IGF-I or 25-OH vitamin D. Osteocalcin and PTH were positively correlated when samples from all seasons were pooled and when only hibernation samples were considered, raising the possibility that the anabolic actions of PTH help maintain bone formation to prevent disuse osteoporosis. Prostaglandin E(2) (PGE(2)) release from MC3T3 osteoblastic cells was significantly affected by treatment with bear serum from different seasons (i.e. hibernation versus active periods). The seasonal changes in PGE(2) release showed trends similar to the seasonal changes in serum IGF-I. Since both PGE(2) and IGF-I are associated with collagenous bone formation, it is possible that seasonal changes in a circulating factor influence IGF-I levels in vivo in bears and PGE(2) release in osteoblastic cells in vitro. The significant decrease in serum leptin following arousal from hibernation may promote bone formation during remobilization, assuming there is a similar decrease in intracerebroventricular leptin. These findings support the idea that seasonal changes in the concentration of circulating molecules help regulate bone formation activity and may be important for preventing disuse osteoporosis in bears.