Mast Cells Trigger Disturbed Bone Healing in Osteoporotic Mice

Abstract

Mast cells are important tissue-resident sensor and effector immune cells but also play a major role in osteoporosis development. Mast cells are increased in numbers in the bone marrow of postmenopausal osteoporotic patients, and mast cell-deficient mice are protected from ovariectomy (OVX)-induced bone loss. In this study, we showed that mast cell-deficient Mcpt5-Cre R-DTA mice were protected from OVX-induced disturbed fracture healing, indicating a critical role for mast cells in the pathomechanisms of impaired bone repair under estrogen-deficient conditions. We revealed that mast cells trigger the fracture-induced inflammatory response by releasing inflammatory mediators, including interleukin-6, midkine (Mdk), and C-X-C motif chemokine ligand 10 (CXCL10), and promote neutrophil infiltration into the fracture site in OVX mice. Furthermore, mast cells were responsible for reduced osteoblast and increased osteoclast activities in OVX mice callus, as well as increased receptor activator of NF-κB ligand serum levels in OVX mice. Additional in vitro studies with human cells showed that mast cells stimulate osteoclastogenesis by releasing the osteoclastogenic mediators Mdk and CXCL10 in an estrogen-dependent manner, which was mediated via the estrogen receptor alpha on mast cells. In conclusion, mast cells negatively affect the healing of bone fractures under estrogen-deficient conditions. Hence, targeting mast cells might provide a therapeutic strategy to improve disturbed bone repair in postmenopausal osteoporosis.

Mast Cells Drive Systemic Inflammation and Compromised Bone Repair After Trauma

“…However, nothing is known about their involvement in trauma-induced compromised bone repair, which is frequently observed in multiply injured patients ( 2 ). Thereby, we focused on the early inflammatory phase, which is strongly affected by the additional trauma, and on the later repair phase, which serves as a read-out for successful fracture healing, and where mast cells were already shown to play an important role during fracture repair ( 26 , 29 ). In agreement with previous experimental studies ( 7 , 11 , 13 , 17 , 26 , 39 – 42 ), the model of combined fracture and thoracic trauma used in the present study induced an increased systemic inflammation after 3 h in mast cell-competent mice as indicated by elevated serum IL-6, CXCL-10, MCP-3, IL-5 and eotaxin levels.…”

“…Furthermore, mast cell-deficient mice displayed diminished IL-6 levels and improved coronary inflammation in response to stress-induced trauma ( 56 ). In addition, systemic inflammatory mediator levels, including IL-6 and CXCL-10, were reduced in mast cell-deficient mice during regular and ovariectomy-induced compromised bone repair, indicating that mast cells contribute to fracture-induced inflammation ( 26 , 29 ). Mast cell stabilization using cromolyn in mice improved the outcome of ischemic-reperfusion injury associated with reduced blood IL-6 and TNF levels ( 24 ).…”

“…Moreover, mast cells might contribute to bone formation and callus remodeling during bone repair ( 27 , 28 ), because they were shown, for example, to stimulate osteoclast formation and activity during fracture callus resorption ( 26 ). Recently, we additionally revealed that mast cells were responsible for the increased fracture-induced systemic and local inflammatory response and for compromised healing in osteoporotic bone ( 29 , 30 ). These data suggest that mast cells regulate inflammation and repair during bone fracture healing.…”

The Rising Era of “Immunoporosis”: Role of Immune System in the Pathophysiology of Osteoporosis

“…Another study demonstrated that female mice lacking mast cell chymase Mcpt4 showed higher serum bone anabolic markers and a higher periosteal bone formation rate 60 suggesting the functional effect of mast cell chymase on bone health. Recently, a study was reported by Fischer et al 61 in a MCs deficient Mcpt5-Cre-R-DTA mice model where deficiency of MCs protected mice from Ovx-induced osteoporosis and perturbed fracture healing, indicating a crucial role of MCs in the pathophysiology of osteoporosis under estrogen-deficient conditions. In wild-type conditions, MCs triggered fracture provoked an inflammatory response by promoting release of inflammatory molecules IL-6, CXCL10, and midkine (Mdk) along with inducing the infiltration of neutrophils at the fracture site in ovariectomized mice.…”

“…In wild-type conditions, MCs triggered fracture provoked an inflammatory response by promoting release of inflammatory molecules IL-6, CXCL10, and midkine (Mdk) along with inducing the infiltration of neutrophils at the fracture site in ovariectomized mice. 61 IL-31, secreted by MCs, are also being employed as biomarker to monitor disease severity in various allergic diseases. Interestingly, a study reported that increased levels of IL-31 in post-menopausal osteoporotic patients are correlated with reduced BMD.…”