Abstract
The main driver of osteoporosis is an imbalance between bone resorption and formation. The pathogenesis of osteoporosis has also been connected to genetic alterations in key osteogenic factors and dysfunction of bone marrow mesenchymal stem/stromal cells (BM-MSCs). Tks4 (encoded by the Sh3pxd2b gene) is a scaffold protein involved in podosome organization. Homozygous mutational inactivation of Sh3pxd2b causes Frank-ter Haar syndrome (FTHS), a genetic disease that affects bone tissue as well as eye, ear, and heart functions. To date, the role of Tks4 in adult bone homeostasis has not been investigated. Therefore, the aim of this study was to analyze the facial and femoral bone phenotypes of Sh3pxd2b knock-out (KO) mice using micro-CT methods. In addition to the analysis of the Sh3pxd2b-KO mice, the bone microstructure of an FTHS patient was also examined. Macro-examination of skulls from Tks4-deficient mice revealed craniofacial malformations that were very similar to symptoms of the FTHS patient. The femurs of the Sh3pxd2b-KO mice had alterations in the trabecular system and showed signs of osteoporosis, and, similarly, the FTHS patient also showed increased trabecular separation/porosity. The expression levels of the Runx2 and osteocalcin bone formation markers were reduced in the bone and bone marrow of the Sh3pxd2b-KO femurs, respectively. Our recent study demonstrated that Sh3pxd2b-KO BM-MSCs have a reduced ability to differentiate into osteoblast lineage cells; therefore, we concluded that the Tks4 scaffold protein is important for osteoblast formation, and that it likely plays a role in bone cell homeostasis.
Highlights
The main driver of osteoporosis is an imbalance between bone resorption and formation
We performed systematic assessments of the cranioskeleton and searched for equivalent structures in the Sh3pxd2b-KO mice and the Frank-ter Haar syndrome (FTHS) patient[17]. These analyses revealed several cranial malformations shared by the Tks4-deficient mice and the FTHS patient (Fig. 1f)
We previously demonstrated that tyrosine kinase substrate (Tks)[4] is expressed in bone marrow (BM) mesenchymal stem/stroma cells (BM-mesenchymal stem/stromal cell (MSC)) and that MSCs derived from Sh3pxd2b-KO mice have a reduced capacity to differentiate into osteoblastic cells
Summary
The main driver of osteoporosis is an imbalance between bone resorption and formation. Our recent study demonstrated that Sh3pxd2b-KO BM-MSCs have a reduced ability to differentiate into osteoblast lineage cells; we concluded that the Tks[4] scaffold protein is important for osteoblast formation, and that it likely plays a role in bone cell homeostasis. Several phenotypes of the Sh3pxd2b-KO C57Bl/6 mice recapitulate FTHS pathologies, including craniomaxillofacial malformations, growth retardation (manifested by reduced long bone size and body mass), glaucoma and kyphosis[13]; like FTHS patients, the Tks4-deficient mice develop heart failure. The abnormal bone morphology observed in the FTHS patients and the Sh3pxd2b-KO mice is a hallmark of the Tks[4] mutant phenotype, the roles of Tks[4] in in situ bone structure maintenance and bone homeostasis have not been investigated. The Tks4-mutant mice exhibited an osteoporotic phenotype, suggesting that the Tks[4] scaffold protein is involved in osteoporotic processes
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