Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments.
Bone morphogenetic protein (BMP) signaling pathways play critical roles in skeletal development and new bone formation. Our previous study, however, showed a negative impact of BMP signaling on bone mass because of the osteoblast-specific loss of a BMP receptor (i.e. BMPR1A) showing increased trabecular bone volume and mineral density in mice. Here, we investigated the bone quality and biomechanical properties of the higher bone mass associated with BMPR1A deficiency using the osteoblast-specific Bmpr1a conditional knockout (cKO) mouse model. Collagen biochemical analysis revealed greater levels of the mature cross-link pyridinoline in the cKO bones, in parallel with upregulation of collagen modifying enzymes. Raman spectroscopy distinguished increases in the mature to immature cross-link ratio and mineral to matrix ratio in the trabecular compartments of cKO femora, but not in the cortical compartments. The mineral crystallinity was unchanged in the cKO in either the trabecular or cortical compartments. Further, we tested the intrinsic material properties by nanoindentation and found significantly higher hardness and elastic modulus in the cKO trabecular compartments, but not in the cortical compartments. Four point bending tests of cortical compartments showed lower structural biomechanical properties (i.e. strength and stiffness) in the cKO bones due to the smaller cortical areas. However, there were no significant differences in biomechanical performance at the material level, which was consistent with the nanoindentation test results on the cortical compartment. These studies emphasize the pivotal role of BMPR1A in the determination of bone quality and mechanical integrity under physiological conditions, with different impact on femoral cortical and trabecular compartments.
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA.
Yanshuai
Y
Zhang
Biomedical Engineering, College of Engineering, University of Michigan, MI, USA.
Erin Gatenby
EG
McNerny
School of Dentistry, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
Masahiko
M
Terajima
Department of Chemistry, College of Literature, Science and the Arts, University of Michigan, MI, USA.
Mekhala
M
Raghavan
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA.
Genevieve
G
Romanowicz
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA.
Zhanpeng
Z
Zhang
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA.
Honghao
H
Zhang
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA; Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA; Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Faculty of Budo and Sport Studies, Tenri University, Nara, Japan.
Nobuhiro
N
Kamiya
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA.
Margaret
M
Tantillo
Department of Chemistry, College of Literature, Science and the Arts, University of Michigan, MI, USA.
Peizhi
P
Zhu
Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Gregory J
GJ
Scott
Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Manas K
MK
Ray
Office of Research, School of Dentistry, University of Michigan, MI, USA.
Michelle
M
Lynch
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA.
Peter X
PX
Ma
Department of Chemistry, College of Literature, Science and the Arts, University of Michigan, MI, USA.
Michael D
MD
Morris
School of Dentistry, University of North Carolina at Chapel Hill, North Carolina, NC, USA.
Mitsuo
M
Yamauchi
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA; Biomedical Engineering, College of Engineering, University of Michigan, MI, USA.
David H
DH
Kohn
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA; Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA; Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. Electronic address: mishina@umich.edu.
Yuji
Y
Mishina
D000818:Animals; D001696:Biomechanical Phenomena; D001857:Bone Matrix / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D000071556:Cancellous Bone / Q000378:metabolism* / Q000502:physiology; D003094:Collagen / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000378:metabolism*; D055119:Elastic Modulus; D005269:Femur / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation; D006244:Hardness; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
D019485:Bone Morphogenetic Proteins; D003432:Cross-Linking Reagents; D003094:Collagen; D052005:Bone Morphogenetic Protein Receptors, Type I
BMP receptor type 1A; Biomechanical properties; Bone quality; Collagen cross-links; Cortical geometry