Matrix Metalloproteinases in Relation to Bone Mineral Density: A Two-Sample Mendelian Randomization Study

Abstract

Background: We aimed at investigating causal associations between matrix metalloproteinases (MMPs) and bone mineral density (BMD) by the Mendelian randomization (MR) analysis.Methods: From genome-wide association studies of European ancestry, we selected instrumental variables for MMP-1, MMP-3, MMP-7, MMP-8, MMP-10, and MMP-12. Accordingly, we retrieved summary statistics of three site-specific BMD, namely, forearm, femoral neck, and lumbar spine. We conducted an inverse variance weighted MR as the primary method to compute overall effects from multiple instruments, while additional MR approaches and sensitivity analyses were implemented. Bonferroni-adjusted significance threshold was set at p < 0.05/18 = 0.003.Results: Totally, there was no evidence for causal effects of genetically-predicted levels of MMPs on BMD measurement at three common sites. MR results indicated that there were no causal associations of circulating MMPs with forearm BMD (all p ≥ 0.023) by the inverse variance weighted method. Similarly, there were no causal effects of MMPs on femoral neck BMD (all p ≥ 0.120) and MR results did not support causal relationships between MMPs and lumbar spine BMD (all p ≥ 0.017). Multiple sensitivity analyses suggested the robustness of MR results, which were less likely to be biased by unbalanced pleiotropy or evident heterogeneity.Conclusion: We found no evidence for the causal relationship between MMPs and BMD in the European population.

Importance of Metalloproteinase Enzyme Group in Selected Skeletal System Diseases

“…However, there is a paper evaluating serum MMP-8 levels in relation to skeletal characteristics among children and adolescents with obesity. In this study, neither among a control group of children with normal BMI nor among children with obesity was there any correlation between MMP-8 and bone turnover markers such as BALP, CTXm and PINP [131], which would agree with the predictions of Lv et al [123].…”

“…Lv et al [123] conducted an analysis on genetically predicted levels of serum MMPs and concluded that for the European population, MMP-1, MMP-3, MMP-7, MMP-8, MMP-10, and MMP-12 showed no evidence of association with BMD index assessed via DEXA. These predictions appear to be confirmed by results obtained by some research teams around the world.…”

“…-Conflicting data among patients with osteoporosis as the sole disease: (a) genetically predicted serum level is not associated with BMD [123], (b) in postmenopausal women, a higher serum MMP-3 in osteoporotic women than in women with a normal BMD [114,130], (c) in postmenopausal women with osteopenia, the MMP-3 serum level is higher [130] or shows no difference [114] than in women with a normal BMD, (d) in postmenopausal women with osteopenia, the MMP-3 serum level is lower [114] or shows no difference [130] than in osteoporotic women. -Serum MMP-3 among only postmenopausal women: (a) with osteoporosis, it was correlated negatively with BMD and OPGL [114] and positively with OPG [114] and OPN [130], (b) with osteopenia, it was correlated negatively with the BMD of the lumbar spine and ward angle [114].…”

Investigating the association between serum ADAM/ADAMTS levels and bone mineral density by mendelian randomization study

“…They found that Mmp9/Mmp14 conditional double-knockout mice exhibited marked increases in bone density and displayed a highly protected status against either parathyroid hormone- or ovariectomy-induced pathologic bone loss. Inconsistently, our previous two-sample MR analysis found no evidence for the causal relationship between MMPs and BMD in the European population [ 43 ]. Such contradict findings encouraged further explorations in this field.…”