Defective bone repair in mast cell-deficient Cpa3Cre/+ mice

Abstract

In the adult skeleton, cells of the immune system interact with those of the skeleton during all phases of bone repair to influence the outcome. Mast cells are immune cells best known for their pathologic role in allergy, and may be involved in chronic inflammatory and fibrotic disorders. Potential roles for mast cells in tissue homeostasis, vascularization and repair remain enigmatic. Previous studies in combined mast cell- and Kit-deficient KitW-sh/W-sh mice (KitW-sh) implicated mast cells in bone repair but KitW-sh mice suffer from additional Kit-dependent hematopoietic and non- hematopoietic deficiencies that could have confounded the outcome. The goal of the current study was to compare bone repair in normal wild type (WT) and Cpa3Cre/+ mice, which lack mast cells in the absence of any other hematopoietic or non- hematopoietic deficiencies. Repair of a femoral window defect was characterized using micro CT imaging and histological analyses from the early inflammatory phase, through soft and hard callus formation, and finally the remodeling phase. The data indicate 1) mast cells appear in healing bone of WT mice but not Cpa3Cre/+ mice, beginning 14 days after surgery; 2) re-vascularization of repair tissue and deposition of mineralized bone was delayed and dis-organised in Cpa3Cre/+ mice compared with WT mice; 3) the defects in Cpa3Cre/+ mice were associated with little change in anabolic activity and biphasic alterations in osteoclast and macrophage activity. The outcome at 56 days postoperative was complete bridging of the defect in most WT mice and fibrous mal-union in most Cpa3Cre/+ mice. The results indicate that mast cells promote bone healing, possibly by recruiting vascular endothelial cells during the inflammatory phase and coordinating anabolic and catabolic activity during tissue remodeling. Taken together the data indicate that mast cells have a positive impact on bone repair.

Mast Cells Are Critical Regulators of Bone Fracture–Induced Inflammation and Osteoclast Formation and Activity

“…The results of our study are in contrast to a study investigating bone repair in another c‐Kit ‐independent mouse model of MC deficiency . In this study, bone formation rather than bone resorption was disturbed in the absence of MCs.…”

“…Osteoclast numbers were only temporarily decreased. The authors suggested that MCs might have a positive impact on bone repair that is mediated by increased revascularization . In contrast, we actually found a slight increase of the bone fraction in the callus of Mcpt5‐Cre R‐DTA mice on day 7, suggesting that repair might have started slightly earlier because of the overall reduced inflammation in the absence of MCs.…”

“…In 1967, Lindholm and colleagues described a progressive increase of MCs in the periosteal callus in a rat tibial‐fracture model . This was confirmed by other authors, who found an increased MC number in the early soft callus around blood vessels . Notably, MCs were also observed in the later bony callus near bone resorption sites.…”

“…A crucial drawback of this mouse model is that other immune cell populations and osteoclasts are also severely affected because c‐Kit expression is essential for hematopoietic stem‐cell differentiation. Recently, bone defect healing was investigated in c‐Kit‐ independent MC‐deficient Cpa3 Cre/+ mice . The authors found reduced vascularization and bone repair in the absence of MCs, indicating a potential mechanistic role in bone regeneration.…”

The Role of Mast Cells in Bone Metabolism and Bone Disorders

“…Investigations of bone repair in a cortical window defect in a c-Kit-independent Cpa3 Cre/+ mouse model found impaired bone regeneration, as confirmed by reduced cortical bridging, vascularization, and bone mineralization. The authors further observed diminished osteoclast activity at earlier stages, but increased osteoclast activity in the late healing phase (204). Therefore, MC functions in bone repair may comprise blood vessel formation as well as anabolic and catabolic processes during fracture repair and remodeling (Figure 1D).…”