Genetic approaches to metabolic bone diseases

Abstract

Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating concentrations of calcium, phosphate or vitamin D metabolites. These diseases commonly have a genetic basis and represent either a monogenic disorder due to a germline or somatic single gene mutation, or an oligogenic or polygenic disorder that involves variants in more than one gene. Germline single gene mutations causing Mendelian diseases typically have a high penetrance, whereas the genetic variations causing oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. Recognition of familial monogenic disorders is of clinical importance to facilitate timely investigations and management of the patient and any affected relatives. The diagnosis of monogenic metabolic bone disease requires careful clinical evaluation of the large diversity of symptoms and signs associated with these disorders. Thus, the clinician must pursue a systematic approach beginning with a detailed history and physical examination, followed by appropriate laboratory and skeletal imaging evaluations. Finally, the clinician must understand the increasing number and complexity of molecular genetic tests available to ensure their appropriate use and interpretation.

X-linked hypophosphatemic osteomalacia with PHEX mutation presenting late in Pakistan

“…A variety of factors including lack of knowledge and/or experience, lack of resources, or failure to follow recommendations may interfere with a physician's use of effective diagnostic techniques, preventive measures, and timely managements. Although genetic tests are crucial to the diagnosis of many rare bone diseases [ 5 ] the ordering of a specific test or set of tests typically depends on a clinician's evaluation and ability to recognize clues pointing to conditions for which genetic testing may be warranted. However, availability of genetic testing in Pakistan is only available at few places, but the initial stages of diagnosis still depend on classic clinical practices including patient history, physical examination, use of laboratory investigations and application of clinical knowledge and reasoning skills.…”

The Emerging Role of MicroRNAs in Bone Diseases and Their Therapeutic Potential

“…As depicted throughout this review, molecular biologists have been working tirelessly to unveil the miRNA-mediated molecular mechanism underlying bone disease pathophysiology. However, many unsolved questions regarding the genetic etiology of bone diseases deserve further analysis in the forthcoming years, e.g., a wide range of bone disease-associated genes whose miRNA-based regulation has not yet been thoroughly studied; some examples of these genes are CLCN7 , WNT1 , IFITM5 , SERPINF1 , CRTAP , PSL3 , COL1A1, and COL1A2 [ 159 , 160 ]. In the same sense, diverse investigations have demonstrated the importance of multiple miRNAs in bone development, such as miR-10b, miR-19a-3p, miR-26b, miR-92a, miR-130a, miR-135-5p, and miR-374b [ 161 ]; nonetheless, there are few reports about their potential theragnostic roles in bone diseases.…”

“…Nevertheless, more lncRNAs -miRNAs-based research is needed to develop novel therapeutic strategies against bone diseases. In addition, data regarding the implications of the miRNA transcriptome in other less common metabolic bone diseases, such as rickets, fluorosis, hyperparathyroidism, hypophosphatasia, sclerosteosis, and tumor-induced osteomalacia [ 160 , 168 ], are still scarce and hence need to be studied.…”

Drugs for the treatment of metabolic bone diseases

“…In this context, clinical pharmacologists have played major roles in the development of drugs for the treatment of metabolic bone diseases. However, clinical pharmacologists also have the potential to exert additional influence on the optimal use of existing agents going forward, both through the improved use of clinical and translational pharmacokinetics and pharmacodynamics as described in this issue by Riggs et al, as well as via astute implementation of tools derived from our evolving understanding of the role that genetics plays in metabolic bone diseases, as described by Hannan et al in this issue.…”

“…Aberrant genetics play a causal role in many of the more than 400 described rare bone diseases . In this issue, Hannan et al describe how our increasing understanding of genetics is providing new paradigms for diagnosis and treatment, as well as for the discovery, translation, and clinical development of new drugs targeting these severely debilitating rare skeletal diseases. Similarly, contributions in this issue describe the discovery and clinical developmental efforts for new drugs designed to treat the rare bone diseases fibrous dysplasia, osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and X‐linked hypophosphatemia …”