Causal association between cathepsins and bone mineral density : univariate and multivariate Mendelian randomization analyses

doi:10.21203/rs.3.rs-3883845/v1

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Causal association between cathepsins and bone mineral density : univariate and multivariate Mendelian randomization analyses

https://doi.org/10.21203/rs.3.rs-3883845/v1

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Background: Bone mineral density (BMD) is one of the criteria for assessing osteoporosis, and the mechanisms of its change are complex. However, cathepsins can intervene in the onset and progression of osteoporosis. Previous researchers have found an association between cathepsin K and BMD in middle-aged and older people. However, the association between the cathepsin family and other lifecycle BMD remains uncertain.

Method: We first performed univariateMendelian randomisation (MR) analysis to explore potential the association between eight cathepsins and five lifecycle BMD. Next, reverse MR was used to analyze the causality between five lifecycle BMD and each cathepsin. Finally, we used multivariate MR to analyze potential associationbetween multiple cathepsins and five lifecycle BMD. Analysis method uses inverse variance weighting (IVW) to assess causal associations. The weighted median method (WME) and MR-Egger regression were taken as the supplementary note. In addition, sensitivity analyses were performed to assess the reliability of this result.

Result: The results of IVW by univariate MR analysis showed that histone enzyme Z was a unfavourable protein for BMD in people aged 60 over years of age (IVW: OR=0.95, 95%Cl=0.92-0.99, P=0.03). In people aged 45-60 years, cathepsin H was a risk protein for BMD (IVW: OR =0.97, 95%Cl =0.94-0.99, P=0.04). The remaining cathepsins showed no associations associated with BMD at different life stages. The IVW results of multivariate MR analysis showed that after adjusting for other cathepsins, cathepsin Z was still negatively correlated with BMD in people aged 60 over years (IVW: OR=0.96, 95%Cl=0.92-1.00, P=0.01). Cathepsin H had no correlated with BMD in people aged 45-60 years (IVW: OR=0.97, 95%Cl=0.93-1.00, P=0.06). The results of IVW in the reverse MR analysis showed no association between cathepsins and BMD at different life stages. The results of the sensitivity analyses of the three analytical methods described above indicate the existence of a robust causal relationship.

Conclusions: High content of histone enzyme Z may increase the risk of osteoporosis and fractures in people over the age of 60. This finding may not only improve the accuracy of BMD and cathepsin K in predicting and screening for osteoporosis, but may also provide a potential new avenue for effective treatment of osteoporosis.

Osteoporosis

Bone mineral density

Lifecycle

Cathepsin

Accuracy

Health skeletal is a prominent component of the musculoskeletal system in humans and animals, and its function is to support the body and provide energy for muscle attachment and movement (Buckwalter et al 1996). Bone mineral density (BMD) is a significant biological indicator of the quality of bone health (Chen et al 2023). However, BMD values vary at different life stages (Medina et al 2018). There is rapid growth in early childhood, eventually reaching peak in adulthood (Deng et al 2021). During aging, changes in visceral function and hormone levels can disrupt bone homeostasis mechanisms, leading to changes in skeletal (Wu et al 2015, Lee et al 2023). Skeletal changes not only increase the likelihood of multisite arthritis, but also the likelihood of osteoporotic fractures (Sanderson et al 2022).

Cathepsins have been shown to be involved in processes such as bone homeostatic mechanisms, immune responses and extracellular matrix degradation (Yadati et al 2020). In a study on the association between cathepsin K and BMD, cathepsin K content was found to be significantly lower in middle-aged and older adults with low BMD than in healthy individuals (Mittal et al 2018). At the same time, Geum-Hwa also found a negative association between cathepsin K and BMD In the osteoporotic 32-week-old rat model experiment (Lee et al 2023). Although cathepsin K has been shown to be associated with BMD in middle and old age. However, cathepsins are a large family and the association between other cathepsins and BMD at different life stages remains undetermined due to various experimental constraints.

With the advances in genetics, genetics has become a larger and larger part of the etiology of disease. Although randomized controlled trial (RCT) has high reference significance, it cannot be carried out generally due to multiple clinical factors (Clayton et al 2023). However, MR is a kind of genetic variation as a tool variable, follow Mondel's law, namely the corresponding allele in the formation of random allocation and fixed principle, eliminate the influence of mixed factors, to strengthen the causality of evidence strength, can achieve the purpose of simulation RCT (Nazarzadeh et al 2020, Lawlor et al 2008). In this context, we chose this statistical tool to analyse and elucidate the association between other cathepsins and BMD at different stages of life.

study design and sources

Our study used two-sample, Reverse and multivariable MR methods. Firstly univariate statistical analysis can elucidate the potential causal relationship of cathepsin family on BMD at different life stages. All subjects were restricted to European ancestry, partly reducing the bias in population stratification. Next, multivariate MR was used to determine the direct effect of a specific type of cathepsins independently of other cathepsins on the risk of outcome BMD. Finally, we used reverse MR to elucidate the causal relationship of exposure and outcome. Our study design followed multiple hypotheses. (1) IVs are closely linked to cathepsins. (2) IVs were independent of mixed variables and was not associated with other mixed variables affecting the "exposure-outcome". (3) IVs can only affect the BMD through cathepsins, but not by other ways. Figure 1 is a schematic of the direction of our overall research program.

In this study, exposure datas were from the IEU database, with cathepsins in Z, F, E, H, G, L, S and B respectively. Outcome datas were from the IEU database as (0–15, 15–30, 30–45, 45–60, and 60 + years, respectively).

Instrumental variables selection

IVs for MR analysis are selected according to the following criteria: first, the selected IV should be statistically significant (P < 5×10^− 6). Next, set the clustering parameters to R²<0.001 and kb = 10,000kb. Ensure independence between the selected iv and reduce the impact of chain imbalances. Finally, we removed SNPs with f-statistics below 10 (Burress et al, 2011). Formula:

Statistical analysis

This study mainly used IVW because it can obtain a robust result in the presence of polymorphisms (Thompson et al 2013). The MR-egger and WME were used as auxiliary tools to increase the accuracy of the main analysis. The WME provides accurate and reliable effect estimates (Minelli et al 2016a). Sensitivity analyses were performed to assess the reliability of this result. (Haycock et al 2016b, Davey et al 2019). Multivariate MR is an extension of two-sample MR to estimate the causality of multiple cathepsins to BMD at different life stages by incorporating all exposures into the same model. The statistical methods for this study were all performed using the publicly available R software package.

Univariate MR analyzed the relationship between cathepsin families and BMD at ages 0–15, 15–30, 30–45, 45–60 and 60 years and older

We performed univariate statistical analysis using eight cathepsins with BMD at different life stages. In Fig. 2, cathepsin H performed a negative causal relationship with BMD values in 45–60 years (IVW: OR = 0.97, 95% Cl = 0.94-1.00, P = 0.04). Cathepsin Z was negatively correlated with BMB in patients over 60 years old (IVW: OR = 0.95, 95%Cl = 0.92–0.99, P = 0.03). Other ancillary methods further confirmed the reliability of the results (Table 1). Furthermore, sensitivity analyses showed no heterogeneity or pleiotropy in the results of our univariate MR analysis (Supplementary Table S1).

Table 1

The causal relationship between cathepsin and five age groups was estimated by univariate Mendelian randomization analysis
Cathepsin	Inverse variance weighted				MR-egger			Weighted median
Cathepsin	OR(95%CI)		P		OR(95%CI)	P		OR(95%CI)	P
Cathepsin B
age 0–15		0.97(0.92–1.02)		0.20	1.06(0.95–1.18)		0.30	0.97(0.91–1.03)	0.34
age 15–30		1.00(0.92–1.09)		0.97	1.02(0.85–1.23)		0.82	1.00(0.90–1.13)	0.86
age 30–45		1.01(0.96–1.06)		0.73	1.00(0.88–1.12)		0.95	1.00(0.92–1.07)	0.90
age 45–60		0.97(0.93–1.01)		0.13	0.91(0.83−1.00)		0.06	0.95(0.90–0.99)	0.03
over 60		0.95(0.93–1.03)		0.42	0.92(0.82–1.02)		0.14	0.92(0.88–0.97)	0.00
Cathepsin E
age 0–15		1.02(0.96–1.10)		0.55	1.07(0.92–1.25)		0.41	1.00(0.92–1.09)	0.95
age 15–30		1.01(0.89–1.15)		0.84	0.83(0.61–1.13)		0.27	1.00(0.84–1.10)	0.98
age 30–45		1.00(0.92–1.08)		1.00	1.09(0.91–1.30)		0.36	1.00(0.91–1.11)	0.92
age 45–60		1.00(0.93–1.08)		0.99	0.85(0.74–0.9)		0.03	1.01(0.93–1.10)	0.71
over 60		1.03(0.98–1.09)		0.28	0.99(0.88–1.12)		0.89	1.00(0.93–1.07)	0.94
Cathepsin F
age 0–15		1.01(0.96–1.07)		0.70	1.08(0.93–1.25)		0.32	1.05(0.98–1.13)	0.15
age 15–30		0.95(0.86–1.04)		0.26	1.00(0.75–1.32)		0.99	0.97(0.86–1.11)	0.68
age 30–45		0.98(0.91−1.00)		0.55	0.99(0.81–1.20)		0.91	0.99(0.90–1.01)	0.78
age 45–60		0.97(0.91–1.03)		0.26	1.04(0.88–1.21)		0.69	0.98(0.92–1.05)	0.66
over 60		0.97(0.93–1.02)		0.21	1.01(0.89–1.15)		0.88	1.00(0.94–1.05)	0.94
Cathepsin G
age 0–15		1.01(0.94–1.09)		0.73	1.01(0.85–1.22)		0.88	0.99(0.90–1.10)	0.87
age 15–30		1.07(0.94–1.22)		0.28	1.08(0.80–1.45)		0.63	1.04(0.88–1.24)	0.61
age 30–45		1.08(0.99–1.18)		0.08	0.99(0.81–1.21)		0.94	1.09(0.97–1.22)	0.16
age 45–60		1.03(0.98–1.10)		0.25	1.01(0.89–1.15)		0.87	1.05(0.97–1.13)	0.25
over 60		1.02(0.97–1.08)		0.41	1.05(0.92–1.20)		0.45	1.02(0.95–1.10)	0.52
Cathepsin H
age 0–15		0.98(0.94–1.03)		0.43	0.96(0.90–1.02)		0.25	0.98(0.93–1.02)	0.35
age 15–30		1.00(0.94–1.06)		0.93	1.02(0.93–1.10)		0.71	1.01(0.94–1.08)	0.78
age 30–45		0.99(0.95–1.03)		0.70	1.03(0.98–1.09)		0.24	1.01(0.97–1.05)	0.62
age 45–60		0.97(0.94−1.00)		0.04	0.99(0.95−1.00)		0.03	0.97(0.94–0.99)	0.01
over 60		1.02(0.96–1.05)		0.92	1.03(0.97–1.10)		0.35	1.01(0.99–1.04)	0.30
Cathepsin S
age 0–15		0.97(0.93−1.00)		0.09	0.98(0.92–1.05)		0.57	0.98(0.92–1.03)	0.39
age 15–30		1.00(0.93–1.08)		0.95	0.94(0.84–1.06)		0.35	1.01(0.91–1.11)	0.88
age 30–45		1.00(0.96–1.04)		0.97	0.98(0.91–1.05)		0.53	1.01(0.95–1.07)	0.77
age 45–60		1.00(0.96–1.03)		0.86	0.99(0.93–1.05)		0.68	0.99(0.95–1.03)	0.55
over 60		1.00(0.97–1.02)		0.84	0.97(0.92–1.02)		0.25	0.98(0.94–1.02)	0.38
Cathepsin L
age 0–15		1.05(0.97–1.13)		0.23	1.19(1.00−1.41)		0.08	1.03(0.93–1.14)	0.58
age 15–30		0.99(0.84–1.17)		0.88	1.21(0.83–1.77)		0.35	0.95(0.79–1.15)	0.62
age 30–45		1.01(0.93–1.09)		0.85	0.92(0.76–1.11)		0.39	0.98(0.88–1.09)	0.70
age 45–60		0.94(0.93–1.05)		0.74	0.96(0.84–1.10)		0.57	1.02(0.94–1.10)	0.63
over 60		0.99(0.93–1.05)		0.69	0.93(0.80–1.09)		0.39	0.98(0.91–1.06)	0.64
Cathepsin Z
age 0–15		1.04(0.99–1.08)		0.12	1.03(0.97–1.11)		0.36	1.05(1.00−1.10)	0.06
age 15–30		0.96(0.89–1.04)		0.31	0.89(0.80−1.00)		0.08	0.96(0.86–1.07)	0.44
age 30–45		1.00(0.97–1.06)		0.77	1.07(1.00−1.16)		0.45	1.06(1.00−1.13)	0.25
age 45–60		1.00(0.96–1.05)		0.88	0.95(0.90–1.01)		0.12	0.99(0.94–1.03)	0.55
over 60		0.95(0.92–0.99)		0.03	0.94(0.91–0.97)		0.01	0.95(0.90–0.97)	0.01

Reverse MR analysis of the results of the association between cathepsin families and BMD in people aged 0–15, 15–30, 30–45, 45–60, and 60 years and older

To assess the association between BMD and cathepsin at different stages of life. We performed reverse statistical analysis. In Supplementary Table S2, there was a lack of reverse causality between eight cathepsins and BMD at different life stages. The auxiliary analysis in Supplementary Table S3 further verified the reliability of the results.

Multivariate MR analysis of the association between cathepsin families and BMD in people aged 0–15, 15–30, 30–45, 45–60 and 60 years and older

As shown in Fig. 3, after adjusting for other cathepsins, cathepsin Z still showed a negatively causal relationship with BMD in patients over 60 years old (IVW: OR = 0.96,95%Cl = 0.92-1.00, P = 0.01). Cathepsin H had no correlated with BMD in people between the ages of 45 and 60 years (IVW: OR = 0.97,95%Cl = 0.93-1.00, P = 0.06). The results of other cathepsin analyses are shown in Table 2. In addition, sensitivity analyses revealed no heterogeneity or pleiotropy in the results of our multivariate Mr analysis(Supplementary Table S4).

Table 2

The causal relationship between cathepsin and five age groups was estimated by multivariate Mendelian randomization analysis
Cathepsin	Nsnp
age 0–15
CathepsinB	16.00	0.96	0.92–1.01	0.09
CathepsinE	11.00	1.02	0.95–1.09	0.65
CathepsinF	11.00	0.99	0.93–1.05	0.65
CathepsinG	11.00	1.00	0.94–1.07	0.90
CathepsinH	11.00	0.97	0.93–1.01	0.10
CathepsinS	21.00	0.95	0.91–0.99	0.01
CathepsinL	21.00	1.04	0.98–1.11	0.22
CathepsinZ	12.00	1.03	0.97–1.08	0.31
age 15–30
CathepsinB	16.00	0.99	0.91–1.08	0.81
CathepsinE	11.00	1.00	0.88–1.14	0.97
CathepsinF	11.00	0.97	0.87–1.09	0.61
CathepsinG	11.00	1.04	0.92–1.16	0.54
CathepsinH	11.00	1.01	0.94–1.08	0.84
CathepsinS	21.00	1.02	0.95–1.10	0.60
CathepsinL	21.00	1.01	0.89–1.13	0.93
CathepsinZ	12.00	0.99	0.90–1.09	0.81
age 30–45
CathepsinB	16.00	1.01	0.96–1.06	0.81
CathepsinE	11.00	1.03	0.95–1.11	0.50
CathepsinF	11.00	0.95	0.89–1.01	0.10
CathepsinG	11.00	1.08	1.01–1.15	0.05
CathepsinH	11.00	0.99	0.95–1.03	0.55
CathepsinS	21.00	0.99	0.95–1.03	0.62
CathepsinL	21.00	1.01	0.94–1.08	0.76
CathepsinZ	12.00	1.08	1.02–1.14	0.82
age 45–60
CathepsinB	16.00	0.98	0.94–1.02	0.32
CathepsinE	11.00	0.99	0.93–1.07	0.85
CathepsinF	11.00	1.00	0.94–1.06	0.89
CathepsinG	11.00	0.98	0.92–1.04	0.44
CathepsinH	11.00	0.97	0.93–1.01	0.06
CathepsinS	21.00	1.01	0.97–1.05	0.63
CathepsinL	21.00	0.96	0.90–1.02	0.19
CathepsinZ	12.00	0.99	0.94–1.04	0.71
over 60
CathepsinB	16.00	0.98	0.94–1.02	0.39
CathepsinE	11.00	1.01	0.95–1.08	0.68
CathepsinF	11.00	0.97	0.92–1.02	0.27
CathepsinG	11.00	1.06	1.00−1.12	0.05
CathepsinH	11.00	1.01	0.97–1.04	0.73
CathepsinS	21.00	0.99	0.95–1.03	0.62
CathepsinL	21.00	1.02	0.96–1.07	0.60
CathepsinZ	12.00	0.96	0.92−1.00	0.01

BMD is a significant assessment of skeletal health, predicting fracture risk and osteoporosis (Gani et al 2023). It is closely related to age, gender, hormones, medication, etc (Cui et al 2019, Salari et al 2021). With age, the expression of various hormones and proteins in the body is different, and BMD is in a changing range. However, mechanisms of bone homeostasis are important causes of pathological and physiological changes in BMD (Zhang et al 2023). Bone resorption plays a significant role in the mechanism, originating from hormone-stimulating signals, such as parathyroid hormone (Branstetter et al 2023). Bone resorption includes the demeralization of bone inorganic components and the degradation of bone organic components, among which there are three main cathepsins attend tothe degradation of bone organic matrix: cysteine protease, matrix metalloproteinases and neutrophil serine elastase. However, cysteine proteases play a dominant role in bone organic matrix-degrading cathepsins. One study showed that 90% of the bone organic matrix is made up of insoluble type I collagen fibres. Cysteine proteases can degrade type I collagen fibres in human cortical bone independently and completely in the absence of other proteases, resulting in changes in bone mass (Shorey et al 2004). Both bone destruction and bone resorption caused by inflammation are also responsible for the changes of BMD. Kassem found that the cysteine protease inhibitor cystatin C inhibited Tumor necrosis factor expression and effectively inhibited osteoclastogenesis induced by LPS in vitro and in vivo (Kassem et al 2017). These experiments validate that cysteine proteases display a prominent role in skeletal metabolism and may serve as novel potential biomarkers of osteoporosis.

Based on the above study, we comprehensively analysed the association of eight cathepsins with BMD at different life stages using instrumental variables of genetic variation. By integrating the results of univariate, multivariate, and inverse analyses, Our team found that histone enzyme Z is a risk factor for BMD, particularly in people over 60 years of age, and we did not find reverse causality for cathepsin Z. Statistically, the results derived from IVV were consistent with the other auxiliary analyses and no heterogeneity or pleiotropy was found. However, observational studies have found that cathepsin Z is still associated with people over the age of 50. Current statistical methods for MR do not support this view. Our team results suggest that cathepsin Z is not associated with BMD in the 45–60 age group. This may be due to the split in the age range. Meanwhile, our univariate analysis found an association between cathepsin H and BMD in the 45–60 age group. No statistical significance was found when other proteases were corrected in the multivariate analysis. This suggests that the finding should be treated with caution.

Previous studies have demonstrated a significant effect of cathepsin Z on osteoporosis and fracture incidence (Ranganath et al 2019). cathepsin Z, a cysteine protease, has a unique chromosomal location and is involved in intracellular protein modification (Deussing et al, 2000). In a study investigating the genetic factors associated with the development of fragility fractures in osteoporosis patients treated with oestrogen inhibitors, single nucleotide polymorphisms were found within or near the three cathepsin Z gene clusters (Goss et al 2014). Another study of the association between altered histone Z mRNA levels in human peripheral blood mononuclear cells and patients with osteoporosis found that the mRNA was strongly associated with low bone mineral density, particularly in women with osteoporosis over the age of 50. The study also found that elevated mRNA levels may be associated with peripheral blood mononuclear cells (Ranganath et al 2019). However, the role of peripheral blood mononuclear cells in osteoporosis, although recognised, is still not fully understood (Dar et al 2018). This undoubtedly adds to the complexity of the mechanisms by which histone Z affects BMD, and more research is needed to elucidate its role in BMD.

Osteoporosis screening is becoming increasingly popular as the aging population increases. The biochemical parameters of the test and screening for osteoporosis offer significant advantages in terms of simplicity and speed. This study validated the association by integrating univariate, multivariate and reverse MR, which has the advantage of avoiding reverse causality and confounding, and saves time and resources compared with observational studies; secondly, this study did not reveal any potential horizontal pleiotropy, thus confirming the reliability of the conclusions; However, our study has several shortcomings: first, our study only observed an association of cathepsin Z at the genetic level in people over 60 years of age, and there was no association in people between 45 and 60 years of age, which is somewhat inconsistent with many published observational studies. In the future, MRI studies with larger samples and randomised controlled trials are needed to verify the results. Second, as with all published MR studies, the possibility of unobserved pleiotropy influencing the results cannot be excluded, even if measures are taken to identify and eliminate aberrant variants. Finally, the selected population was European and it is not yet possible to demonstrate whether the results are applicable to other groups.

In conclusion, this study shows that High content of histone enzyme Z may increase the risk of osteoporosis and fractures in people over the age of 60. This finding may not only improve the accuracy of BMD and cathepsin K in predicting and screening for osteoporosis, but may also provide a potential new avenue for effective treatment of osteoporosis.

This study was supported by The Third Affiliated Hospital of Beijing University of Chinese Medicine (BZYSY-2022-PYMS-18 )

Author Contribution

Yun-Hui Zhang A.B.Jing-Yan Yang A.B.Jun-De Wu E.F.Ying-Wang E.F.Shao-Jia Chen E.F.Xing-Jing Mo E.F.Hui Guo1 E.F.Rui-Zheng zhu E.F.Zhao-Jun Chen E.F.

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No competing interests reported.

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Causal association between cathepsins and bone mineral density : univariate and multivariate Mendelian randomization analyses

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