TRPV4 deficiency causes sexual dimorphism in bone metabolism and osteoporotic fracture risk

• Published in: Bone (New York, N.Y.) Vol. 57; no. 2; pp. 443 - 454
• Main Authors: van der Eerden, B.C.J, Oei, L, Roschger, P, Fratzl-Zelman, N, Hoenderop, J.G.J, van Schoor, N.M, Pettersson-Kymmer, U, Schreuders-Koedam, M, Uitterlinden, A.G, Hofman, A, Suzuki, M, Klaushofer, K, Ohlsson, C, Lips, P.J.A, Rivadeneira, F, Bindels, R.J.M, van Leeuwen, J.P.T.M
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-12-2013; Elsevier
• Subjects: Animals; ATES OF AMERICA; Biological and medical sciences; Bone; Bone and Bones - metabolism; Bone and Bones - pathology; CALCIUM; CORTICAL POROSITY; DENSITY DISTRIBUTION; Diseases of the osteoarticular system; DISTAL RADIUS; Elastic Modulus; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Fracture risk; Fundamental and applied biological sciences. Psychology; Genetic Association Studies; Genetic Predisposition to Disease; GROWTH; HOMEOSTASIS; Humans; Injuries of the limb. Injuries of the spine; Male; Medical sciences; MICE; MINERAL DENSITY; Netherlands - epidemiology; NETICS; Orthopedics; OSTEOBLAST DIFFERENTIATION; Osteoblasts - pathology; Osteoclasts - pathology; Osteoporosis; Osteoporosis. Osteomalacia. Paget disease; Osteoporotic Fractures - epidemiology; Osteoporotic Fractures - genetics; P17507; P190; Phenotype; Polymorphism, Single Nucleotide - genetics; RECEPTOR; Risk Factors; Sex Characteristics; Sexual dimorphism; Stress, Mechanical; STRUCTURAL BASIS; Traumas. Diseases due to physical agents; TRPV Cation Channels - deficiency; TRPV Cation Channels - genetics; TRPV4; V102; V160C; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Netherlands; Osteoporosis; Bone; Sexual dimorphism; Fracture risk; TRPV4; Deficiency; Morphology; Diseases of the osteoarticular system; Risk factor; Fracture; Metabolism; Trauma
• ISSN: 8756-3282; 1873-2763; 1873-2763
• DOI: 10.1016/j.bone.2013.09.017

Abstract We explored the role of transient receptor potential vanilloid 4 (TRPV4) in murine bone metabolism and association of TRPV4 gene variants with fractures in humans. Urinary and histomorphometrical analyses demonstrated reduced osteoclast activity and numbers in male Trpv4−/− mice, which was confirmed in bone marrow-derived osteoclast cultures. Osteoblasts and bone formation as shown by serum procollagen type 1 amino-terminal propeptide and histomorphometry, including osteoid surface, osteoblast and osteocyte numbers were not affected in vivo . Nevertheless, osteoblast differentiation was enhanced in Trpv4−/− bone marrow cultures. Cortical and trabecular bone mass was 20% increased in male Trpv4−/− mice, compared to sex-matched wild type ( Trpv4+/+ ) mice. However, at the same time intracortical porosity was increased and bone matrix mineralization was reduced. Together, these lead to a maximum load, stiffness and work to failure of the femoral bone, which were not different compared to Trpv4+/+ mice, while the bone material was less resistant to stress and less elastic. The differential impacts on these determinants of bone strength were likely responsible for the lack of any changes in whole bone strength in the Trpv4−/− mice. None of these skeletal parameters were affected in female Trpv4−/− mice. The T-allele of rs1861809 SNP in the TRPV4 locus was associated with a 30% increased risk (95% CI: 1.1–1.6; p = 0.013) for non-vertebral fracture risk in men, but not in women, in the Rotterdam Study. Meta-analyses with the population-based LASA study confirmed the association with non-vertebral fractures in men. This was lost when the non-population-based studies Mr. OS and UFO were included. In conclusion, TRPV4 is a male-specific regulator of bone metabolism, a determinant of bone strength, and a potential risk predictor for fractures through regulation of bone matrix mineralization and intra-cortical porosity. This identifies TRPV4 as a unique sexually dimorphic therapeutic and/or diagnostic candidate for osteoporosis.