## 2 The Role(s) of Non-Collagenous Bone Matrix Proteins in Bone
### Effects of Non-Collagenous Proteins on Bone Structure and Mechanics
In double knockout models of OC-OPN\({}^{-/-;-/-}\) mice, co-dependent control over mineralization by OPN and OC has been suggested; yet the two proteins seemed to govern independently the morphology of the semicrystalline minerals formed [65]. In addition, even though there were many shared traits in OPN\({}^{-/-}\) and OC\({}^{-/-}\) bone compared to normal WT bone, their deleterious effects on bone ultrastructure and mechanical properties were generally non  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**NCPs and** & **Whole-Bone** & **Ultrastructure** & **Chemistry and** & **Mechanical** & **Related Bone** \\
**References** & **Structure** & **(and Microstructure)** & **Composition** & **Properties\({}^{2}\)** & **Diseases\({}^{3}\)** \\ \hline Tissue-nonspecific alkaline phosphatase & & & & & \\ \(\downarrow\)Hemoral length & & & & & \\ \(\downarrow\) trabecular bone & & & & & \\ \(\uparrow\)crystal misalignment & & & & & \\ \(\uparrow\)Cac concentration & & &  
additive. This is evidenced by results from both quantitative ultrastructural analysis and mechanical testing (Figure 3b,c). Such an observation alludes to the general degeneracies of biological systems and the possible functional redundancies between NCPs mentioned previously [112]. [PERSON] et al. also revealed that the formation of bone minerals remained unimpeded in the absence of both matrix proteins despite defective changes to the crystal shape, dimensions, and orientation [65]. Therefore, it is reasonable to assume that other NCPs may play a similarly important role in bone mineral formation and collagen mineralization. Other commonly studied pairs of NCPs are combinations of SLRPs such as biglyscan (Bgn) and decorin (Dcn). Decorin (Dcn) is highly homologous to Bgn, containing one chondro sulfate chain attached near its amino terminal group instead of two in Bgn. However, the conformational folds for the two NCPs are dissimilar [113]. One would imagine that comparing and contrasting the effects of Bgn- and Dcn-deficiencies on bone quality could offer interesting insights into their functional roles. Unfortunately, there currently exists minimal information on how _bone_ ultrastructure, chemistry, and mechanics are altered in the single knockout Dcn\({}^{-/-}\) despite numerous reports for its close relative Bgn. In one study cross-examining both SLRPs,  
Figure 3: Deficiencies of OPN and OC in bone of knockout mice models. (**a**) Resolving OPN-deficiency-induced ultrastructural changes in bone using TEM (**left**), nanobeam electron diffraction (**middle**), and qBEI imaging (**right**). Figures reprinted from [36,81], with permissions from Elsevier. (**b**) Quantitative analysis on the bone ultrastructure, i.e., mineral crystal thickness and orientation, in WT, OPN\({}^{-/-}\), OC\({}^{-/-}\), and OC-OPN\({}^{-/-}\) mice. Degree of orientation, the so-called \(\rho\)-parameter, is calculated from SAXS patterns. Figures are replotted using data from [65]. (**c**) Mechanical properties of bone in WT, OPN\({}^{-/-}\), OC\({}^{-/-}\), and OC-OPN\({}^{-/-}\) mice: stiffness, ultimate bending strength, propagation toughness, and diffuse damage upon fatigue. Figures are replotted using data from [60,72]. Asterisk * indicates a statistically significant difference compared to WT, with \(p<0.05\). n.s. = not significant. Dcn\({}^{-/-}\) mice retained their bone mass, suggesting the absence of an osteopenia-like state, whereas a reduction in bone mass was recorded for Bgn\({}^{-/-}\) mice [74]. In the same study, the collagen fibril diameter also decreased by 12% for Dcn\({}^{-/-}\) but increased by 10% for Bgn\({}^{-/-}\) compared to the WT control. The irregular collagen formation observed might offer a partial explanation to the association of Dcn-deficiency with osteogenesis imperfeta [114], and additional ultrastructural information is needed but missing in this area. Markedly distinct effects of Bgn and Dcn deficiencies on bone were found, even though highly similar effects were seen in the dermis [74].