Loss of Adipogenic Dickkopf-1 Increases Trabecular and Cortical Bone Mass by Promoting Bone Formation in Male Mice

Introduction Osteoporosis is a frequent disease characterized by a decrease of bone mass and quality leading to a higher risk of fractures. Dickkopf-1 (DKK1) is an inhibitor of Wnt signaling and thereby inhibits osteoblast differentiation and decreases bone mass. In our previous studies we showed that osteogenic cells are the main producers of circulating DKK1. Given that osteoblasts and adipocytes share the same precursor mesenchymal stem cell and that bone marrow adiposity increases with age, we investigated the impact of adipogenic DKK1 deletion on bone homeostasis in mice.

Methods The adipogenic deletion of DKK1 was induced in 6-week-old mice through cre recombinase-loxP system (DKK1f/f; AdipoQ-Cre, cKO) by five subsequent injections of tamoxifen (10 mg/kg). Six weeks later, the body weight and fat pads of cKO and their littermate controls were measured. Bone parameters were assessed by micro-computed tomography, bone turnover markers by using enzyme-linked immunosorbent assays, and biomechanical testing. Each group included 7-20 mice.

Results Female and male adipogenic DKK1 cKO showed a similar body weight compared to control mice. However, males revealed a decrease of the gonadal and subcutaneous fat pads with 16% (p<0.05) and 46% (p<0.05), respectively, compared to control mice. While female cKO mice showed no alterations in bone parameters, male cKO mice showed a 61% increase in femoral trabecular bone volume. The trabecular number increased by 9%, the trabecular thickness by 11%, while trabecular separation was decreased by 10%. The cortical thickness of cKO was increased by 4%. In the fourth lumbar vertebra, trabecular bone volume was increased by 21% and bone mineral density by 14%. Biomechanical tests revealed that cKO mice had a 7% and 8% improvement in femoral and vertebra stiffness, respectively, compared to the control group. Male DKK1 cKO mice showed increased serum levels of P1NP (+75%). Serum CTX was elevated by 32%, while serum TRAcP5b levels were decreased by 16% in DKK1 cKO mice compared to control mice.

Discussion Based on this study, DKK1 derived from adipogenic cells appears to influence adipose tissue expansion and signal in a paracrine way to inhibit bone formation and thereby reduce bone mass.

Keywords DKK1, Adipose tissue, Bone mass, Male mice, Bone formation

Korrespondenzadresse Souad Daamouch, Universitätsklinikum Carl Gustav Carus – Dresden, Universitätsklinikum Dresden, Fetscherstraße 74, 01309 Dresden, Allemagne, E-Mail: [e-mail]

Publication History

Article published online:
08 September 2022