Mechanistic insights into the spontaneous induction of bone formation

Abstract

The grand discovery of morphogens, or "form-generating substances", revealed that tissue morphogenesis is initiated by soluble molecular signals or morphogens primarily belonging to the transforming growth factor-β (TGF-β) supergene family. The regenerative potential of bone rests on its extracellular matrix, which is the repository of several morphogens that tightly control cellular differentiating pathways, cellular matrix deposition and remodeling. Alluringly, the matrix also contains specific factors transferred from the heterotopic implanted bone matrices initiating "Tissue Induction", as provocatively described in Nature in 1945. Later, it was found that selected genes and gene products of the TGF-β supergene family singly, synchronously, and synergistically mastermind the induction of bone formation. This review describes the phenomenon of the spontaneous and/or intrinsic osteoinductivity of calcium phosphate-based biomaterials and titanium' constructs without the applications of soluble osteogenetic molecular signals. The review shows the spontaneous induction of bone formation initiated by Ca++ activating stem cell differentiation and up-regulation of bone morphogenetic proteins genes. Expressed gene products are embedded into the concavities of the calcium phosphate-based substrata, initiating bone formation as a secondary response. Pure titanium's substrata do not initiate the spontaneous induction of bone formation. The induction of bone is solely dependent on acid, alkali and heat treatments to form apatite layers on the treated titanium surfaces. The induction of bone formation is achieved exclusively by apatite-based biomaterial surfaces. The hydroxyapatite, in its various forms and geometric configurations, finely tunes the induction of bone formation in heterotopic sites. Cellular differentiation by fine-tuning of the cellular molecular machinery is initiated by specific geometric modularity of the hydroxyapatite substrata that push cellular buttons that start the ripple-like cascade of "Tissue Induction", generating newly formed ossicles with bone marrow in heterotopic extraskeletal sites. The highlighted mechanistic insights into the spontaneous induction of bone formation are a research platform invocating selected molecular elements to construct the induction of bone formation.

Keywords: Bone morphogenetic proteins; Ca ++; Cell engineering; Embedding molecular signals; Geometry; Noggin; Spontaneous and/or intrinsic osteoinductivity; Titanium and bone induction; Transforming growth factor-β proteins.