A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis
Abstract:Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserv… Show more
“…Although HBM is likely to be caused by the polygenic inheritance of multiple BMD loci [ 12 ], or the monogenic inheritance of rare variants [ 42 ], indicating that HBM precedes OA development, we cannot rule out the possibility that biological pleiotropy, rather than a causal effect, explains our results. We have previously identified an increased prevalence of pelvic enthesophytes in the HBM population, leading to the hypothesis that HBM individuals may have a genetic predisposition to form extra bone [ 43 ].…”
Background
Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes.
Methods
We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering.
Results
Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM βosteophyte = 0.30 [0.01, 0.58], p = 0.019 and βJSN = 0.10 [0.01, 0.18], p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (β = 8.3 [0.7, 15.98], p = 0.032).
Conclusions
HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.
“…Although HBM is likely to be caused by the polygenic inheritance of multiple BMD loci [ 12 ], or the monogenic inheritance of rare variants [ 42 ], indicating that HBM precedes OA development, we cannot rule out the possibility that biological pleiotropy, rather than a causal effect, explains our results. We have previously identified an increased prevalence of pelvic enthesophytes in the HBM population, leading to the hypothesis that HBM individuals may have a genetic predisposition to form extra bone [ 43 ].…”
Background
Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes.
Methods
We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering.
Results
Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM βosteophyte = 0.30 [0.01, 0.58], p = 0.019 and βJSN = 0.10 [0.01, 0.18], p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (β = 8.3 [0.7, 15.98], p = 0.032).
Conclusions
HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.
“…Whereas SMAD1 and SMAD5 activate transcription in this context, SMAD9 acts as a transcriptional repressor ( Tsukamoto et al, 2014 ). Notably, SMAD9 loss-of-function mutations lead to increased bone mineral density and cortical thickness, resulting in greater bone strength but not HO, as in FOP ( Gregson et al, 2020 ). Fig.…”
Heterotopic ossification (HO) is a disorder characterised by the formation of ectopic bone in soft tissue. Acquired HO typically occurs in response to trauma and is relatively common, yet its aetiology remains poorly understood. Genetic forms, by contrast, are very rare, but provide insights into the mechanisms of HO pathobiology. Fibrodysplasia ossificans progressiva (FOP) is the most debilitating form of HO. All patients reported to date carry heterozygous gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1). These mutations cause dysregulated bone morphogenetic protein (BMP) signalling, leading to HO at extraskeletal sites including, but not limited to, muscles, ligaments, tendons and fascia. Ever since the identification of the causative gene, developing a cure for FOP has been a focus of investigation, and studies have decoded the pathophysiology at the molecular and cellular levels, and explored novel management strategies. Based on the established role of BMP signalling throughout HO in FOP, therapeutic modalities that target multiple levels of the signalling cascade have been designed, and some drugs have entered clinical trials, holding out hope of a cure. A potential role of other signalling pathways that could influence the dysregulated BMP signalling and present alternative therapeutic targets remains a matter of debate. Here, we review the recent FOP literature, including pathophysiology, clinical aspects, animal models and current management strategies. We also consider how this research can inform our understanding of other types of HO and highlight some of the remaining knowledge gaps.
“…A study on zebrafish helped to unravel the role of Smad9 as a downstream inhibitor of the BMP signaling pathway and reducer of osteoblast activity, providing evidence that Smad9 can be used as anabolic target for the treatment of osteoporosis. A loss-of-function SMAD9 mutation reduces BMP inhibition which, in turn, allows enhanced bone formation through the positive regulation of RUNX2 by BMP2 [ 70 ]. OP-like symptoms can also be induced in wild type or bone transgenic zebrafish using the glucocorticoid dexamethasone; this model has been extensively used in recent years to test potential pharmacological treatments, which in zebrafish, can be easily performed on a large scale.…”
Section: Zebrafish and Human Bone Diseasesmentioning
In recent decades, many studies using the zebrafish model organism have been performed. Zebrafish, providing genetic mutants and reporter transgenic lines, enable a great number of studies aiming at the investigation of signaling pathways involved in the osteoarticular system and at the identification of therapeutic tools for bone diseases. In this review, we will discuss studies which demonstrate that many signaling pathways are highly conserved between mammals and teleost and that genes involved in mammalian bone differentiation have orthologs in zebrafish. We will also discuss as human diseases, such as osteogenesis imperfecta, osteoarthritis, osteoporosis and Gaucher disease can be investigated in the zebrafish model.
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