TY - JOUR
T1 - Widespread disturbance in extracellular matrix collagen biomarker responses to teriparatide therapy in osteogenesis imperfecta
AU - Nicol, Lindsey
AU - Srikanth, Priya
AU - Henriksen, Kim
AU - Sun, Shu
AU - Smith, Rosamund
AU - Karsdal, Morten A.
AU - Nagamani, Sandesh C.S.
AU - Shapiro, Jay
AU - Lee, Brendan
AU - Leder, Benjamin Z.
AU - Orwoll, Eric
N1 - Funding Information:
This article is the result of work supported with institutional resources at Oregon Health & Science University. The Osteogenesis Imperfecta Foundation provided funding support through its Seed Grant for Clinical Research program. Eli Lilly and Co. provided funding for the assays through its investigator-initiated support program. We would also like to thank the OHSU Biostatistics & Design Program (partially supported by UL1TR002369 [OHSU CTSA]) for data analysis expertise.
Funding Information:
Jay Shapiro and Priya Srikanth have no conflicts of interest to disclose. Lindsey Nicol is a sub-investigator on a clinical research study sponsored by Mereo and receives travel funding from the OI foundation. Brendan Lee and Sandesh Nagamani receive research support from Sanofi-Genzyme for OI-related research and travel funding from the OI foundation. Sandesh Nagamani is an investigator on clinical trials in OI sponsored by Amgen and Mereo. Kim Henriksen (KH), Shu Sun, and Morten Karsdal (MK) are employees of Nordic Bioscience and have patents on the biomarkers. KH and MK also hold stock in Nordic Bioscience. Rosamund Smith is a retired employee of Eli Lilly and owns Eli Lilly stock and has issued patents that belong to Eli Lilly. Benjamin Leder has received research funding from Eli Lilly. Eric Orwoll is a research consultant for Bayer, Amgen, Radius and Biocon, receives research support from Mereo, and travel funding from the OI Foundation.
Funding Information:
This article is the result of work supported with institutional resources at Oregon Health & Science University. The Osteogenesis Imperfecta Foundation provided funding support through its Seed Grant for Clinical Research program. Eli Lilly and Co. provided funding for the assays through its investigator-initiated support program. We would also like to thank the OHSU Biostatistics & Design Program (partially supported by UL1TR002369 [OHSU CTSA]) for data analysis expertise. Jay Shapiro and Priya Srikanth have no conflicts of interest to disclose. Lindsey Nicol is a sub-investigator on a clinical research study sponsored by Mereo and receives travel funding from the OI foundation. Brendan Lee and Sandesh Nagamani receive research support from Sanofi-Genzyme for OI-related research and travel funding from the OI foundation. Sandesh Nagamani is an investigator on clinical trials in OI sponsored by Amgen and Mereo. Kim Henriksen (KH), Shu Sun, and Morten Karsdal (MK) are employees of Nordic Bioscience and have patents on the biomarkers. KH and MK also hold stock in Nordic Bioscience. Rosamund Smith is a retired employee of Eli Lilly and owns Eli Lilly stock and has issued patents that belong to Eli Lilly. Benjamin Leder has received research funding from Eli Lilly. Eric Orwoll is a research consultant for Bayer, Amgen, Radius and Biocon, receives research support from Mereo, and travel funding from the OI Foundation.
Publisher Copyright:
© 2020
PY - 2021/1
Y1 - 2021/1
N2 - Osteogenesis imperfecta (OI), a heritable disorder caused by abnormalities in synthesis or processing of type I collagen, is characterized by skeletal fragility. Type I collagen interacts with multiple components of the extracellular matrix (ECM) including other collagens types. Thus, alterations in structure or quantity may broadly affect ECM homeostasis. In fact, while OI is clinically categorized by severity of bone disease, patients can also present with extra-skeletal manifestations, including the pulmonary, muscle and cardiovascular systems. Parathyroid hormone (PTH) is a regulator of skeletal homeostasis but the receptor for PTH/PTH1R is expressed in a variety of other tissues. Given interactions between type I collagen with other collagens in the ECM and the potential for PTH action on tissues beyond the skeleton, we explored whether serum levels of non-type I collagens are altered in response to teriparatide (human parathyroid hormone 1–34). We measured biomarkers of collagens II, III, IV, V, and VI in serum from individuals with type I and types III/IV OI in response to an 18 month course of teriparatide or placebo. These results were compared to similar biomarker measures in postmenopausal (PM) women without OI treated with teriparatide. In type I OI, teriparatide therapy increased concentrations of biomarkers of collagens II, III, IV, V, and VI. In individuals with types III/IV OI these biomarker changes in response to teriparatide were blunted, as we previously reported with collagen I biomarkers during teriparatide therapy. In contrast to OI, in PM women there were no effects of teriparatide on the collagen biomarkers we assessed (II, V, and VI). These findings suggest that in OI teriparatide therapy has abnormal effects on the homeostasis of many ECM collagens likely derived from skeletal as well as extra-skeletal tissues.
AB - Osteogenesis imperfecta (OI), a heritable disorder caused by abnormalities in synthesis or processing of type I collagen, is characterized by skeletal fragility. Type I collagen interacts with multiple components of the extracellular matrix (ECM) including other collagens types. Thus, alterations in structure or quantity may broadly affect ECM homeostasis. In fact, while OI is clinically categorized by severity of bone disease, patients can also present with extra-skeletal manifestations, including the pulmonary, muscle and cardiovascular systems. Parathyroid hormone (PTH) is a regulator of skeletal homeostasis but the receptor for PTH/PTH1R is expressed in a variety of other tissues. Given interactions between type I collagen with other collagens in the ECM and the potential for PTH action on tissues beyond the skeleton, we explored whether serum levels of non-type I collagens are altered in response to teriparatide (human parathyroid hormone 1–34). We measured biomarkers of collagens II, III, IV, V, and VI in serum from individuals with type I and types III/IV OI in response to an 18 month course of teriparatide or placebo. These results were compared to similar biomarker measures in postmenopausal (PM) women without OI treated with teriparatide. In type I OI, teriparatide therapy increased concentrations of biomarkers of collagens II, III, IV, V, and VI. In individuals with types III/IV OI these biomarker changes in response to teriparatide were blunted, as we previously reported with collagen I biomarkers during teriparatide therapy. In contrast to OI, in PM women there were no effects of teriparatide on the collagen biomarkers we assessed (II, V, and VI). These findings suggest that in OI teriparatide therapy has abnormal effects on the homeostasis of many ECM collagens likely derived from skeletal as well as extra-skeletal tissues.
KW - Biomarkers
KW - Collagen
KW - Osteogenesis imperfecta
KW - Teriparatide
UR - http://www.scopus.com/inward/record.url?scp=85094981708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85094981708&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2020.115703
DO - 10.1016/j.bone.2020.115703
M3 - Article
C2 - 33099032
AN - SCOPUS:85094981708
SN - 8756-3282
VL - 142
JO - Bone
JF - Bone
M1 - 115703
ER -