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Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss
Juliane Lehmann1,2, Sylvia Thiele1,2, Ulrike Baschant1,2
1Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.
Abstract:
The Wnt inhibitor Dickkopf-1 (DKK1) is a negative regulator of bone formation and bone mass and is dysregulated in various bone diseases. How DKK1 contributes to postmenopausal osteoporosis, however, remains poorly understood. Here, we show that mice lacking DKK1 in T cells are protected from ovariectomy-induced bone loss. Ovariectomy activated CD4+ and CD8+ T cells and increased their production of DKK1. Co-culture of activated T cells with osteoblasts inhibited Wnt signaling in osteoblasts, leading to impaired differentiation. Importantly, DKK1 expression in T cells also controlled physiological bone remodeling. T-cell-deficient Dkk1 knock-out mice had a higher bone mass with an increased bone formation rate and decreased numbers of osteoclasts compared with controls, a phenotype that was rescued by adoptive transfer of wild-type T cells. Thus, these findings highlight that T cells control bone remodeling in health and disease via their expression of DKK1.
Insights
T cells regulate bone mass by producing Dickkopf-1 (DKK1), a Wnt inhibitor. Blocking T cell DKK1 protects against osteoporosis, revealing a novel therapeutic target for bone diseases.
Area of Science:
- Immunology
- Bone Biology
- Endocrinology
Background:
- Dickkopf-1 (DKK1) is a Wnt pathway inhibitor crucial for bone formation and mass.
- DKK1 dysregulation is implicated in various bone diseases, but its role in postmenopausal osteoporosis is unclear.
- T cells are increasingly recognized for their involvement in bone metabolism.
Purpose of the Study:
- To investigate the role of T cell-derived DKK1 in postmenopausal osteoporosis.
- To elucidate the mechanism by which T cells influence bone remodeling.
- To identify T cells as a potential therapeutic target for bone loss.
Main Methods:
- Generation of mice lacking DKK1 specifically in T cells.
- Ovariectomy to induce postmenopausal osteoporosis model.
- Co-culture assays of activated T cells and osteoblasts.
- Analysis of Wnt signaling, osteoblast differentiation, bone mass, and remodeling markers.
- Adoptive transfer of wild-type T cells into Dkk1 knockout mice.
Main Results:
- Mice lacking T cell DKK1 were protected from ovariectomy-induced bone loss.
- Ovariectomy activated T cells (CD4+ and CD8+) and increased their DKK1 production.
- Co-culture demonstrated that T cell DKK1 inhibits osteoblast differentiation via Wnt signaling.
- T cell DKK1 deficiency led to higher bone mass and altered bone remodeling rates in physiological conditions.
- Adoptive transfer of wild-type T cells reversed the bone mass phenotype in T cell-deficient Dkk1 knockout mice.
Conclusions:
- T cells regulate bone remodeling in both health and disease through DKK1 production.
- T cell-derived DKK1 is a key mediator of bone loss in postmenopausal osteoporosis.
- Targeting T cell DKK1 represents a potential therapeutic strategy for osteoporosis and other bone diseases.
