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The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis by regulating osteoblastic bone formation and osteoclastic bone resorption. Therefore, TAM receptors emerge as new key players of the regulatory cytokine network of osteoblasts and osteoclasts and represent accessible targets for pharmacologic therapy for a broad set of different bone diseases, including primary and metastatic bone tumors, rheumatoid arthritis, or osteoporosis.

Mast cells may contribute to osteoporosis development, because patients with age-related or post-menopausal osteoporosis exhibit more mast cells in the bone marrow, and mastocytosis patients frequently suffer from osteopenia. We previously showed that mast cells crucially regulated osteoclastogenesis and bone loss in ovariectomized, estrogen-depleted mice in a preclinical model for post-menopausal osteoporosis and found that granular mast cell mediators were responsible for these estrogen-dependent effects. However, the role of the key regulator of osteoclastogenesis, namely, receptor activator of NFκB ligand (RANKL), which is secreted by mast cells, in osteoporosis development has, to date, not been defined. Here, we investigated whether mast-cell-derived RANKL participates in ovariectomy (OVX)-induced bone loss by using female mice with a conditional Rankl deletion. We found that this deletion in mast cells did not influence physiological bone turnover and failed to protect against OVX-induced bone resorption in vivo, although we demonstrated that RANKL secretion was significantly reduced in estrogen-treated mast cell cultures. Furthermore, Rankl deletion in mast cells did not influence the immune phenotype in non-ovariectomized or ovariectomized mice. Therefore, other osteoclastogenic factors released by mast cells might be responsible for the onset of OVX-induced bone loss.

There is evidence that mast cells contribute to inflammation induced by hemorrhagic shock, severe tissue injury or sepsis. Mast cells are highly responsive to alarm signals generated after trauma, and release many inflammatory mediators including interleukin-6, a key mediator of posttraumatic inflammation. An overwhelming posttraumatic inflammation causes compromised bone healing; however, the underlying cellular and molecular mechanisms are poorly understood. Recently, we found that mast cells trigger local and systemic inflammation after isolated fracture leading to uneventful bone repair. Here, we investigated whether mast cells critically contribute to trauma-induced compromised bone healing. Male Mcpt5-Cre+ R-DTA mice, which lack connective tissue type mast cells, and their mast cell-competent Cre− littermates underwent a femur fracture with/without thoracic trauma. Posttraumatic systemic and local inflammation and bone repair were assessed 3 h and 21 d post injury. Both, the systemic and pulmonary inflammation was significantly increased in mast cell-competent mice upon combined trauma compared to isolated fracture. In mast cell-deficient mice, the increase of inflammatory mediators in the circulation induced by the severe trauma was abolished. In the bronchoalveolar lavage fluid, the trauma-induced increase of inflammatory cytokines was not reduced, but the neutrophil invasion into the lungs was significantly diminished in the absence of mast cells. Locally in the fracture hematoma, mast cell-competent mice displayed reduced inflammatory mediator concentrations after combined trauma compared to isolated fracture, which was abolished in mast cell-deficient mice. Notably, while combined trauma resulted in compromised bone repair in mast cell-competent mice, indicated by significantly reduced bone and increased cartilage fracture callus contents, this was abolished in Mcpt5-Cre+ R-DTA mice. Therefore, mast cells contribute to trauma-induced compromised bone repair and could be a potential target for new treatment options to improve fracture healing in multiply injured patients.

Mast cells (MCs) are important sensor and effector cells of the immune system that are involved in many physiological and pathological conditions. Increasing evidence suggests that they also play an important role in bone metabolism and bone disorders. MCs are located in the bone marrow and secrete a wide spectrum of mediators, which can be rapidly released upon activation of mature MCs following their differentiation in mucosal or connective tissues. Many of these mediators can exert osteocatabolic effects by promoting osteoclast formation [e.g., histamine, tumor necrosis factor (TNF), interleukin-6 (IL-6)] and/or by inhibiting osteoblast activity (e.g., IL-1, TNF). By contrast, MCs could potentially act in an osteoprotective manner by stimulating osteoblasts (e.g., transforming growth factor-β) or reducing osteoclastogenesis (e.g., IL-12, interferon-γ). Experimental studies investigating MC functions in physiological bone turnover using MC-deficient mouse lines give contradictory results, reporting delayed or increased bone turnover or no influence depending on the mouse model used. By contrast, the involvement of MCs in various pathological conditions affecting bone is evident. MCs may contribute to the pathogenesis of primary and secondary osteoporosis as well as inflammatory disorders, including rheumatoid arthritis and osteoarthritis, because increased numbers of MCs were found in patients suffering from these diseases. The clinical observations could be largely confirmed in experimental studies using MC-deficient mouse models, which also provide mechanistic insights. MCs also regulate bone healing after fracture by influencing the inflammatory response toward the fracture, vascularization, bone formation, and callus remodeling by osteoclasts. This review summarizes the current view and understanding of the role of MCs on bone in both physiological and pathological conditions.