- A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders. Formosa MM, Bergen DJM, Gregson CL, Maurizi A, Kämpe A, Garcia-Giralt N, Zhou W, Grinberg D, Ovejero Crespo D, Zillikens MC, Williams GR, Bassett JHD, Brandi ML, Sangiorgi L, Balcells S, Högler W, Van Hul W, Mäkitie O. Front Endocrinol (Lausanne). 2021 Aug 13;12:709711. doi: 10.3389/fendo.2021.709711. PMID: 34539568; PMCID: PMC8444146. Studies on extreme phenotypes have been instrumental in elucidating molecular mechanisms in rare monogenic disorders. However, they have also provided us valuable insights to disease mechanisms in more common chronic diseases, such as osteoporosis, diabetes, and obesity. The rare monogenic phenotypes can be regarded as “human knock-outs” that have the potential of providing unequivocal evidence for involvement of the single gene and pathway in disease pathogenesis. In studies related to extreme bone mass phenotypes, application of an extreme phenotype approach has led to discovery of SOST and LRP5 as critical regulators of WNT signaling in bone and resulted in the development of new drugs to stimulate bone formation. This review provides a roadmap from gene discovery to drug development in rare bone mass phenotypes. We describe how to identify the genetic cause of a monogenic rare bone mass disorder using proper phenotyping and genotyping tools and how the genetic finding can then be validated to uncover mechanisms through which the singe gene defect leads to phenotype. This information can subsequently be used to identify novel drug targets for drug development. Such novel treatments could be used for the specific condition but also more widely to treat e.g., osteoporosis in the general population.
Abnormal Bone Tissue Organization and Osteocyte Lacunocanalicular Network in Early-Onset Osteoporosis Due to SGMS2 Mutations. Mäkitie RE, Blouin S, Välimäki VV, Pihlström S, Määttä K, Pekkinen M, Fratzl-Zelman N, Mäkitie O, Hartmann MA. JBMR Plus. 2021 Aug 20;5(11):e10537. doi: 10.1002/jbm4.10537. PMID: 34761145; PMCID: PMC8567487. Our recent publication describes detailed bone tissue characteristics in patients with a nonsensem mutation p.Arg50* in SGMS2. In 2019, we reported that mutations in the sphingomyelin synthase 2–encoding SGMS2 results in a rare, autosomal dominant skeletal disorder termed Osteoporosis with cranial doughnut lesions (CDL) (Pekkinen et al., JCI Insight 2019). Although aberrant SMS2 function and sphingomyelin metabolism are believed to result in abnormal bone matrix mineralization and consequently severe skeletal fragility, the underlying mechanisms remain incompletely understood. Here we report detailed bone tissue characteristics in two male patients with the same SGMS2 nonsense mutation p.Arg50*. We assessed transiliac bone biopsies from both patients with bone histomorphometry, confocal laser scanning microscopy, and quantitative backscattered electron imaging (qBEI). Our results indicate a severely disrupted bone matrix organization and mineralization with haphazard collagen fibril arrangement. Also, osteocyte lacunae appeared abnormal in size and shape and the canalicular network severely disturbed with short, unconnected canaliculi. These underline a key role for SMS2 in bone matrix mineralization, osteocyte organization and maintenance of skeletal integrity with central relevance in understanding the role and importance of sphingomyelin metabolism in bone health and disease.
An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility. Mäkitie RE, Henning P, Jiu Y, Kämpe A, Kogan K, Costantini A, Välimäki VV, Medina-Gomez C, Pekkinen M, Salusky IB, Schalin-Jäntti C, Haanpää MK, Rivadeneira F, Bassett JHD, Williams GR, Lerner UH, Pereira RC, Lappalainen P, Mäkitie O. JBMR Plus. 2021 Jun 7;5(7):e10509. doi: 10.1002/jbm4.10509. PMID: 34258505; PMCID: PMC8260816. Recently, we identified a novel pathogenic variant in ARHGAP25 in a large Finnish family with severe early-onset osteoporosis and prevalent fractures. ARHGAP25 is a regulator of RhoGTPases, which are small signaling molecules implicated in various cellular functions such as cytoskeletal actin modeling and cell migration. RhoGTPases have been shown to have key regulatory roles in bone cell functions, and murine models for different RhoGTPases exhibit severe osteopetrotic phenotypes. ARHGAP25, however, has not been linked to bone metabolism before.The publication reports a novel finding of a genetic defect in RhoGTPase signaling in human skeletal disease. We describe a large, multi-generational Finnish family with an unusual form of autosomal dominant early-onset skeletal fragility with marked propensity to fracture, low bone turnover and low serum phosphate. Using WES, we identified the genetic cause as a novel heterozygous missense mutation in ARHGAP25. Computational modeling predicted the variant to locate near the protein's critical domain and disrupt its normal function and our functional experiments further indicated a role for ARHGAP25 in cytoskeletal dynamics and membrane ruffling and high expression of Arhgap25 in mouse bone tissues. GWASs have further shown a 5'UTR ARGHAP25 variant to associate with BMD and fracture risk. These findings bring new biological insight and expand our understanding of the molecular mechanisms underlying skeletal pathologies
Phosphate Concentrations and Modifying Factors in Healthy Children From 12 to 24 Months of Age. Koljonen L, Enlund-Cerullo M, Hauta-Alus H, Holmlund-Suila E, Valkama S, Rosendahl J, Andersson S, Pekkinen M, Mäkitie O. . J Clin Endocrinol Metab. 2021 Sep 27;106(10):2865-2875. doi: 10.1210/clinem/dgab495. PMID: 34214153; PMCID: PMC8475199. Phosphate has many important functions in the body related to, for example, energy metabolism and skeletal metabolism. Phosphate metabolism is not as well-characterized as calcium metabolism. Many factors affecting phosphate and its regulation are unknown. This article, therefore, focused on phosphate levels. The VIDI cohort, a unique study of Finnish toddlers and children, allowed the determination of phosphate levels in healthy children aged 1-2 years. This information can be used at a later stage when possibly updating the reference values. No one has previously found that phosphate levels in children aged 1 year are higher than in children aged 2 years. You can find out more about phosphate levels in children aged 1-2 years in this article.
- Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2. Pekkinen M, Terhal PA, Botto LD, Henning P, Mäkitie RE, Roschger P, Jain A, Kol M, Kjellberg MA, Paschalis EP, van Gassen K, Murray M, Bayrak-Toydemir P, Magnusson MK, Jans J, Kausar M, Carey JC, Somerharju P, Lerner UH, Olkkonen VM, Klaushofer K, Holthuis JC, Mäkitie O. JCI Insight. 2019 Apr 4;4(7):e126180. doi: 10.1172/jci.insight.126180. eCollection 2019 Apr 4.
- WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. Laine CM, Joeng KS, Campeau PM, Kiviranta R, Tarkkonen K, Grover M, Lu JT, Pekkinen M, Wessman M, Heino TJ, Nieminen-Pihala V, Aronen M, Laine T, Kröger H, Cole WG, Lehesjoki AE, Nevarez L, Krakow D, Curry CJ, Cohn DH, Gibbs RA, Lee BH, Mäkitie O. N Engl J Med. 2013 May 9;368(19):1809-16. doi: 10.1056/NEJMoa1215458.
- Effect of Higher vs Standard Dosage of Vitamin D3 Supplementation on Bone Strength and Infection in Healthy Infants: A Randomized Clinical Trial. Rosendahl J, Valkama S, Holmlund-Suila E, Enlund-Cerullo M, Hauta-Alus H, Helve O, Hytinantti T, Levälahti E, Kajantie E, Viljakainen H, Mäkitie O, Andersson S. JAMA Pediatr. 2018 Jul 1;172(7):646-654. doi: 10.1001/jamapediatrics.2018.0602.