Old bones can heal with proper signals: Targeting macrophages to stimulate osteoblasts

ROSEMONT, Ill., May 24, 2018 /PRNewswire-USNewswire/ -- Repair and regeneration capacity of skeletal tissues diminishes with age, often leading to delayed or impaired fracture healing. While the cause of diminished healing capacity is probably driven by a concert of many factors, evidence suggests that aged cells retain the capacity for repair when provided the proper signals. Work led by Orthopaedic Research Society members Gurpreet Baht and Benjamin Alman at Duke University has shown that exposure of old mice to circulation of young mice leads to improvements in bone healing, attributed in part to increased osteoblast differentiation in response to signals provided by young circulation.  

Baht and colleagues have determined that M2 macrophages, a macrophage phenotype associated with repair and reduction of inflammation, are important in fracture healing. Through mass spectrometry studies, a list of 'youth factors' and 'aging factors' associated with M2 macrophages were identified. One of the factors, low-density lipoprotein receptor-related protein 1 (LRP1), stood out as a potential candidate to improve fracture repair. LRP1 is a Wnt antagonist that decreases with age and has been implicated in Alzheimer's disease (AD), cardiovascular disease, and cancer. Interestingly, in all three of those diseases, age-related reduction in LRP1 leads to reduced clearance of particular molecules associated with the disease states (e.g. reduced clearance of amyloid-beta proteins in AD).

Working under the hypothesis that loss of LRP1 in macrophages would be associated with reduced osteoblast differentiation and subsequently impaired fracture healing, the team set out to investigate the role of macrophage-derived LRP1 in fracture repair. Initial in vitro work showed that LRP1 was 60% more abundant in media from young bone marrow cells compared with cells from older mice. Osteoblastic potential of bone marrow cells was also increased by incubation with LRP1 during differentiation.

To investigate the role of LRP1 in fracture repair in vivo, a conditional LRP1 knockout mouse driven by the macrophage/granulocyte-specific promoter, LysM-cre was generated. Bone marrow cells from young control and LRP1 knockout mice were transplanted into old mice that had previously been irradiated. Two months after transplant, old mice were subjected to a tibial fracture. A substantial reduction in healing, based on reduced calcified callus volume and increased callus fibrosis, was observed in mice that had received the LRP1 deficient bone marrow.

While further investigation is still required to elucidate the specific role of LRP1 in bone healing, the evidence that LRP1 appears to attenuate tissue repair in aged individuals is noteworthy. When asked about the work Baht noted, "This finding presents exciting possibilities in future discovery of pharmacologic agents able to enhance fracture healing. Currently, we are identifying the biological changes which occur in response to treatment of aged animals with LRP1 protein. We hope to better understand the effects of such a treatment so that we can move such a system closer to a treatment strategy."

Gurpreet Baht is a member of the Orthopaedic Research Society (ORS).  The ORS mission is to advance musculoskeletal research worldwide.

SOURCE Orthopaedic Research Society

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