Increased Bone Mass in Female Mice Lacking Mast Cell Chymase

Abstract

Here we addressed the potential impact of chymase, a mast-cell restricted protease, on mouse bone phenotype. We show that female mice lacking the chymase Mcpt4 acquired a persistent expansion of diaphyseal bone in comparison with wild type controls, reaching a 15% larger diaphyseal cross sectional area at 12 months of age. Mcpt4-/- mice also showed increased levels of a bone anabolic serum marker and higher periosteal bone formation rate. However, they were not protected from experimental osteoporosis, suggesting that chymase regulates normal bone homeostasis rather than the course of osteoporosis. Further, the absence of Mcpt4 resulted in age-dependent upregulation of numerous genes important for bone formation but no effects on osteoclast activity. In spite of the latter, Mcpt4-/- bones had increased cortical porosity and reduced endocortical mineralization. Mast cells were found periosteally and, notably, bone-proximal mast cells in Mcpt4-/- mice were degranulated to a larger extent than in wild type mice. Hence, chymase regulates degranulation of bone mast cells, which could affect the release of mast cell-derived factors influencing bone remodelling. Together, these findings reveal a functional impact of mast cell chymase on bone. Further studies exploring the possibility of using chymase inhibitors as a strategy to increase bone volume may be warranted.

Mast cell chymase decreases the severity of group B Streptococcus infections

“…For example, it has been shown that MCPT4 can have an impact on normal connective tissue homeostasis of the skin, 12 on baseline intestinal barrier function 48 and on bone mass. 49 Mechanistically, these effects can be attributed to chymase’s proteolytic activity when a substrate associated with the disruption of the homeostatic function can be identified. In vitro data with MCPT4-deficient cells have shown that fibronectin may be one of the main physiological targets for chymase.…”

Mast cells signal their importance in health and disease

“…82 For instance, proteases released from mast cells have been linked to angiogenesis in tissue repair, cancer and bone homeostasis, and inflammation in patients with allergic diseases and other inflammatory conditions, such as inflammatory bowel disease and arthritis. 9,[82][83][84][85][86] Mast cells also play protective roles in host defense against parasites and bacteria, as reviewed by Caughey, 82 and in defense of vertebrates to animal venoms, including honey bees, scorpions, and reptile venoms, as reviewed by Tsai et al 87 Venom-induced innate activation of mast cells results in release of proteases, such as Cpa3 and mast cell protease 4 (homolog of human chymase), that neutralize certain venoms and reduce morbidity and mortality to these venoms in mice. 87 Furthermore, venom-specific IgE antibodies and IgE-mediated mast cell responses after re-exposure to venoms contribute to protection against lethal doses of these toxic venoms.…”

Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin

“…This has for instance been demonstrated for chymase, which has been shown to increase intestinal permeability at homeostatic conditions 21 and to decrease bone mass in the absence of any mast cell activation stimulus. 22 Hence, mast cell proteases are biologically active in the tissue both in inflammatory conditions as described below and in the absence of stimuli that cause mast cell degranulation.…”