Skeletal class II and III malocclusions are craniofacial disorders that negatively impact people’s quality of life worldwide. Unfortunately, the growth patterns of skeletal malocclusions and their clinical correction prognoses are difficult to predict largely due to lack of knowledge of their precise etiology. Inspired by the strong inheritance pattern of a specific type of skeletal malocclusion, previous genome-wide association studies (GWAS) were reanalyzed, resulting in the identification of 19 skeletal class II malocclusion-associated and 53 skeletal class III malocclusion-associated genes. Functional enrichment of these genes created a signal pathway atlas in which most of the genes were associated with bone and cartilage growth and development, as expected, while some were characterized by functions related to skeletal muscle maturation and construction. Interestingly, several genes and enriched pathways are involved in both skeletal class II and III malocclusions, indicating the key regulatory effects of these genes and pathways in craniofacial development. There is no doubt that further investigation is necessary to validate these recognized genes’ and pathways’ specific function(s) related to maxillary and mandibular development. In summary, this systematic review provides initial insight on developing novel gene-based treatment strategies for skeletal malocclusions and paves the path for precision medicine where dental care providers can make an accurate prediction of the craniofacial growth of an individual patient based on his/her genetic profile.

Microgravity-induced bone loss results in a 1% bone mineral density loss monthly and can be a mission critical factor in long-duration spaceflight. Biomolecular therapies with dual osteogenic and anti-resorptive functions are promising for treating extreme osteoporosis. We previously confirmed that NELL-like molecule-1 (NELL-1) is crucial for bone density maintenance. We further PEGylated NELL-1 (NELL-polyethylene glycol, or NELL-PEG) to increase systemic delivery half-life from 5.5 to 15.5 h. In this study, we used a bio-inert bisphosphonate (BP) moiety to chemically engineer NELL-PEG into BP-NELL-PEG and specifically target bone tissues. We found conjugation with BP improved hydroxyapatite (HA) binding and protein stability of NELL-PEG while preserving NELL-1’s osteogenicity in vitro. Furthermore, BP-NELL-PEG showed superior in vivo bone specificity without observable pathology in liver, spleen, lungs, brain, heart, muscles, or ovaries of mice. Finally, we tested BP-NELL-PEG through spaceflight exposure onboard the International Space Station (ISS) at maximal animal capacity (n = 40) in a long-term (9 week) osteoporosis therapeutic study and found that BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects. Our results highlight BP-NELL-PEG as a promising therapeutic to mitigate extreme bone loss from long-duration microgravity exposure and musculoskeletal degeneration on Earth, especially when resistance training is not possible due to incapacity (e.g., bone fracture, stroke).

NELL‐1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1‐p15.3 deletion involving the Nell‐1 gene was recently reported in a patient with short stature and delayed fontanelle closure. Here we sought to define the role of Nell‐1 in endochondral ossification by investigating Nell‐1‐specific inactivation in Col2α1 expressing cell lineages. Nell‐1^flox/flox; Col2α1‐Cre⁺ (Nell‐1^Col2α1KO) mice were generated for comprehensive analysis. Nell‐1^Col2α1KO mice were born alive but displayed subtle femoral length shortening. At 1 and 3 months postpartum, Nell‐1 inactivation resulted in dwarfism and premature osteoporotic phenotypes. Specifically, Nell‐1^Col2α1KO femurs and tibias exhibited significantly reduced length, BMD, BV/TV, trabecular number/thickness, cortical volume/thickness/density, and increased trabecular separation. The decreased bone formation rate revealed by dynamic histomorphometry was associated with altered numbers and/or function of osteoblasts and osteoclasts. Furthermore, longitudinal observations by in vivo micro‐CT showed delayed and reduced mineralization at secondary ossification centers in mutants. Histologically, reduced staining intensities of Safranin O, Col‐2, Col‐10, and fewer BrdU‐positive chondrocytes were observed in thinner Nell‐1^Col2α1KO epiphyseal plates along with altered distribution and weaker expression level of Ihh, Patched‐1, PTHrP, and PTHrP receptor. Primary Nell‐1^Col2α1KO chondrocytes also exhibited decreased proliferation and differentiation, and its downregulated expression of the Ihh‐PTHrP signaling molecules can be partially rescued by exogenous Nell‐1 protein. Moreover, intra‐nuclear Gli‐1 protein and gene expression of the Gli‐1 downstream target genes, Hip‐1 and N‐Myc, were also significantly decreased with Nell‐1 inactivation. Notably, the rescue effects were diminished/reduced with application of Ihh signaling inhibitors, cyclopamine or GANT61. Taken together, these findings suggest that Nell‐1 is a pivotal modulator of epiphyseal homeostasis and endochondral ossification. The cumulative chondrocyte‐specific Nell‐1 inactivation significantly impedes appendicular skeletogenesis resulting in dwarfism and premature osteoporosis through inhibiting Ihh signaling and predominantly altering the Ihh‐PTHrP feedback loop. This article is protected by copyright. All rights reserved

Significance: Tendon injury possesses a high morbidity rate and is difficult to achieve a satisfying prognosis with currently available treatment strategies. Current approaches used for tendon healing always lead to the formation of fibrovascular scar tissue, which significantly compromises the biomechanics of the healed tendon. Moreover, the related functional deficiency deteriorates over time with an increased injury recurrence risk. Small leucine-rich proteoglycans (SLRPs) link and interact with collagen fibrils to regulate tendon structure and biomechanics, which can provide a new and promising method in the field of tendon injury management. Recent Advances: The effect of SLRPs on tendon development has been extensively investigated. SLRP deficiency impairs tendon collagen fibril structure and biomechanic properties, while administration of SLRPs generally benefits tendon wound healing and regains better mechanical properties. Critical Issues: Current knowledge on the role of SLRPs in tendon development and regeneration mostly comes from uninjured knockout mice, and mainly focuses on the morphology description of collagen fibril profile and mechanical properties. Little is known about the regulatory mechanism on the molecular level. Future Directions: This article reviews the current knowledge in this highly translational topic and provides an evidence-based conclusion, thereby encouraging in-depth investigations of SLRPs in tendons and the development of SLRP-based treatments for desired tendon healing.