Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture.
Cathepsin S is a cysteine protease that controls adipocyte differentiation and has been implicated in vascular and metabolic complications of obesity. Considering the inverse relation of osteoblasts and adipocytes and their mutual precursor cell, we hypothesized that cathepsin S may also affect osteoblast differentiation and bone remodeling. Thus, the fat and bone phenotypes of young (3 months old) and aged (12 or 18 months old) cathepsin S knock-out (KO) and wild-type (WT) mice were determined. Cathepsin S KO mice had a normal body weight at both ages investigated, even though the amount of subscapular and gonadal fat pads was reduced by 20%. Further, cathepsin S deficiency impaired adipocyte formation (-38%, p<0.001), which was accompanied by a lower expression of adipocyte-related genes and a reduction in serum leptin, IL-6 and CCL2 (p<0.001). Micro-CT analysis revealed an unchanged trabecular bone volume fraction and density, while tissue mineral density was significantly lower in cathepsin S KO mice at both ages. Aged KO mice further had a lower cortical bone mass (-2.3%, p<0.05). At the microarchitectural level, cathepsin S KO mice had thinner trabeculae (-8.3%), but a better connected trabecular network (+24%). Serum levels of the bone formation marker type 1 procollagen amino-terminal-propeptide and osteocalcin were both 2-3-fold higher in cathepsin S KO mice as was the mineralized surface. Consistently, osteogenic differentiation was increased 2-fold along with an increased expression of osteoblast-specific genes. Interestingly, serum levels of C-terminal telopeptide of type I collagen were also higher (+43%) in cathepsin S KO mice as were histological osteoclast parameters and ex vivo osteoclast differentiation. Thus, cathepsin S deficiency alters the balance between adipocyte and osteoblast differentiation, increases bone turnover, and changes bone microarchitecture. Therefore, bone and fat metabolisms should be monitored when using cathepsin S inhibitors clinically.
Division of Endocrinology, Diabetes and Metabolic Bone Diseases, Department of Medicine III, Dresden Technical University Medical Center, Germany.
M
M
Rauner
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
U
U
Föger-Samwald
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
M F
MF
Kurz
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
C
C
Brünner-Kubath
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
D
D
Schamall
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
A
A
Kapfenberger
Vienna University of Technology, Austria.
P
P
Varga
Krankenhaus der Barmherzigen Brüder, Vienna, Austria.
S
S
Kudlacek
Medical University of Vienna, Vienna, Austria.
A
A
Wutzl
Medical University of Vienna, Vienna, Austria.
H
H
Höger
Vienna University of Technology, Austria.
P K
PK
Zysset
Harvard Medical School, Boston, USA.
G P
GP
Shi
Division of Endocrinology, Diabetes and Metabolic Bone Diseases, Department of Medicine III, Dresden Technical University Medical Center, Germany; Center for Regenerative Therapies Dresden, Germany.
L C
LC
Hofbauer
University of Veterinary Medicine Vienna, Austria.
W
W
Sipos
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria. Electronic address: peter.pietschmann@meduniwien.ac.at.
P
P
Pietschmann
D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000648:ultrastructure*; D002403:Cathepsins / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology*; D060888:Real-Time Polymerase Chain Reaction; D055114:X-Ray Microtomography
D002403:Cathepsins; C028217:cathepsin S
Adipocyte; Bone remodeling; Cathepsin S; Osteoblast; Osteoclast