Inherited and Related Disorders of Bone Matrix Synthesis in Men

Osteoclasts are derived from monocyte/macrophage precursors. Mesenchymal cell commitment to osteoclast development involves the monocyte precursor granulocyte-macrophage colony forming cells responding to the cytokines MCSF, PU.i, the MITF transcription factor and members of the c-FOS family. However, it is the RANK/RANK ligand/osteoprotegerin group stemming from osteoblasts and activated T cells acting through the NF-kB pathway that are the major factors influencing osteoclast multinucleation and differentiation. Considering the multiplicity of factors involved in osteoblast and osteoclast development, it is reasonable to hypothesize that mutations involving certain of these factors will explain bone disorders that are considered "idiopathic" at this time. Cleidocranial dysplasia, a disorder of bone modeling due to haploinsufficiency of Runx2, is an example of a skeletal disorder secondary to mutations involving the major transcription factors regulating osteoblast development. Another level of complexity is defining the relationship of genotype to phenotype. To date, this correlation has not been defined for several of these disorders. As typified by genotype/phenotype relationships in osteogenesis imperfecta, there is considerable overlap in clinical expression in the presence of mutations assumed by their location, mechanism by which the size of deletions or specific amino acid substitutions lead to either mild or severe disease.