Osteogenesis Imperfecta: A Need to Understand Divergent Treatment Outcomes in a Disorder Rich in Heterogeneity

Kozloff, Kenneth M.

doi:10.1002/jbmr.3647

Cited by 6 publications

(5 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present study suggests a similarity of action independent of genetic mutation in the most prominent phenotypic features—calvarial thickness and intracranial volume. Whether similar treatment responses would occur across multiple OI models remains unknown and contributes to the need for the field to better understand diverging outcomes in this disorder …”

Section: Discussionmentioning

confidence: 99%

“…Whether similar treatment responses would occur across multiple OI models remains unknown and contributes to the need for the field to better understand diverging outcomes in this disorder. (62) Our study was initially designed to examine the effect of Scl-Ab over a period of rapid long-bone growth. (10) However, approximately 80% of overall cranial growth in mice occurs during 7 to 14 days of age.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Scheiber

Barton

Khoury

et al. 2019

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

Sclerostin antibody (Scl‐Ab) is an anabolic bone agent that has been shown to increase bone mass in clinical trials of adult diseases of low bone mass, such as osteoporosis and osteogenesis imperfecta (OI). Its use to decrease bone fragility in pediatric OI has shown efficacy in several growing mouse models, suggesting translational potential to pediatric disorders of low bone mass. However, the effects of pharmacologic inhibition of sclerostin during periods of rapid growth and development have not yet been described with respect to the cranium, where lifelong deficiency of functioning sclerostin leads to patterns of excessive bone growth, cranial compression, and facial palsy. In the present study, we undertook dimensional and volumetric measurements in the skulls of growing Brtl/+ OI mice treated with Scl‐Ab to examine whether therapy‐induced phenotypic changes were similar to those observed clinically in patients with sclerosteosis or Van Buchem disorder. Mice treated between 3 and 14 weeks of age with high doses of Scl‐Ab show significant calvarial thickening capable of rescuing OI‐induced deficiencies in skull thickness. Other changes in cranial morphology, such as lengths and distances between anatomic landmarks, intracranial volume, and suture interdigitation, showed minimal effects of Scl‐Ab when compared with growth‐induced differences over the treatment duration. Treatment‐induced narrowing of foramina was limited to sites of vascular but not neural passage, suggesting patterns of local regulation. Together, these findings reveal a site specificity of Scl‐Ab action in the calvaria with no measurable cranial nerve impingement or brainstem compression. This differentiation from the observed outcomes of lifelong sclerostin deficiency complements reports of Scl‐Ab treatment efficacy at other skeletal sites with the prospect of minimal cranial secondary complications. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Scheiber

Barton

Khoury

et al. 2019

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…The variable responses of these molecularly distinct OI mouse models to potential therapeutic agents was evident in other studies employing therapeutic ligands like TGF-β and sclerostin neutralizing antibodies, thus further necessitating a precision medicine approach to treating OI (Grafe et al, 2016;Kozloff, 2019;. More importantly, the evidence from these studies further validate myostatin's potency in muscle regulation.…”

Section: Osteogenesis Imperfectamentioning

confidence: 90%

Deciphering Myostatin’s Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases

Omosule

Phillips

2021

Front. Genet.

View full text Add to dashboard Cite

Current research findings in humans and other mammalian and non-mammalian species support the potent regulatory role of myostatin in the morphology and function of muscle as well as cellular differentiation and metabolism, with real-life implications in agricultural meat production and human disease. Myostatin null mice (mstn−/−) exhibit skeletal muscle fiber hyperplasia and hypertrophy whereas myostatin deficiency in larger mammals like sheep and pigs engender muscle fiber hyperplasia. Myostatin’s impact extends beyond muscles, with alterations in myostatin present in the pathophysiology of myocardial infarctions, inflammation, insulin resistance, diabetes, aging, cancer cachexia, and musculoskeletal disease. In this review, we explore myostatin’s role in skeletal integrity and bone cell biology either due to direct biochemical signaling or indirect mechanisms of mechanotransduction. In vitro, myostatin inhibits osteoblast differentiation and stimulates osteoclast activity in a dose-dependent manner. Mice deficient in myostatin also have decreased osteoclast numbers, increased cortical thickness, cortical tissue mineral density in the tibia, and increased vertebral bone mineral density. Further, we explore the implications of these biochemical and biomechanical influences of myostatin signaling in the pathophysiology of human disorders that involve musculoskeletal degeneration. The pharmacological inhibition of myostatin directly or via decoy receptors has revealed improvements in muscle and bone properties in mouse models of osteogenesis imperfecta, osteoporosis, osteoarthritis, Duchenne muscular dystrophy, and diabetes. However, recent disappointing clinical trial outcomes of induced myostatin inhibition in diseases with significant neuromuscular wasting and atrophy reiterate complexity and further need for exploration of the translational application of myostatin inhibition in humans.

show abstract

“…( 5 ) The divergent treatment outcomes echo several recent studies suggesting the influence of mutation and disease severity on treatment efficacy in OI. ( 62 ) In models of moderate ( +/G610C ) and severe ( Col1a1 Jrt/+ and Crtap −/− ) OI, whether caused by dominant ( +/G610C and Col1a1 Jrt/+ ) collagen or recessive ( Crtap −/− ) mutations, pharmacologic inhibition of sclerostin, an inhibitory ligand to bone formation, improved bone mass and strength. ( 48,50,52 ) In contrast, +/G610C and Crtap −/− mice both respond to TGF‐β inhibition, while the Col1a1 Jrt/+ mouse does not.…”

Section: Discussionmentioning

confidence: 99%

Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta

Omosule

Gremminger

Aguillard

et al. 2020

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Osteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by compromised skeletal integrity, altered microarchitecture, and bone fragility. Current OI treatment strategies focus on bone antiresorptives and surgical intervention with limited effectiveness, and thus identifying alternative therapeutic options remains critical. Muscle is an important stimulus for bone formation. Myostatin, a TGF‐β superfamily myokine, acts through ActRIIB to negatively regulate muscle growth. Recent studies demonstrated the potential benefit of myostatin inhibition with the soluble ActRIIB fusion protein on skeletal properties, although various OI mouse models exhibited variable skeletal responses. The genetic and clinical heterogeneity associated with OI, the lack of specificity of the ActRIIB decoy molecule for myostatin alone, and adverse events in human clinical trials further the need to clarify myostatin's therapeutic potential and role in skeletal integrity. In this study, we determined musculoskeletal outcomes of genetic myostatin deficiency and postnatal pharmacological myostatin inhibition by a monoclonal anti‐myostatin antibody (Regn647) in the G610C mouse, a model of mild–moderate type I/IV human OI. In the postnatal study, 5‐week‐old wild‐type and +/G610C male and female littermates were treated with Regn647 or a control antibody for 11 weeks or for 7 weeks followed by a 4‐week treatment holiday. Inhibition of myostatin, whether genetically or pharmacologically, increased muscle mass regardless of OI genotype, although to varying degrees. Genetic myostatin deficiency increased hindlimb muscle weights by 6.9% to 34.4%, whereas pharmacological inhibition increased them by 13.5% to 29.6%. Female +/mstn +/G610C (Dbl.Het) mice tended to have similar trabecular and cortical bone parameters as Wt showing reversal of +/G610C characteristics but with minimal effect of +/mstn occurring in male mice. Pharmacologic myostatin inhibition failed to improve skeletal bone properties of male or female +/G610C mice, although skeletal microarchitectural and biomechanical improvements were observed in male wild‐type mice. Four‐week treatment holiday did not alter skeletal outcomes. © 2020 American Society for Bone and Mineral Research (ASBMR).

show abstract

Osteogenesis Imperfecta: A Need to Understand Divergent Treatment Outcomes in a Disorder Rich in Heterogeneity

Cited by 6 publications

References 12 publications

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

Deciphering Myostatin’s Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases

Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta

Contact Info

Product

Resources

About